Journal of the Neurological Sciences, 1976, 29:267-275
267
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
REACTIVE H Y P E R G L Y C A E M I A IN PATIENTS W I T H A C U T E S T R O K E
ELDAD MELAMED Department of Neurology, Hadassah University Hospital and Hebrew University - - Hadassah Medical School, Jerusalem (Israel)
(Received 4 February, 1976)
SUMMARY Initial and follow-up fasting serum glucose levels following acute stroke were evaluated retrospectively in 392 selected hospitalized patients. Transitory reactive hyperglycaemia was observed in a large number of patients (28 ~ of the total series) without a history of diabetes prior to the acute cerebrovascular event. The data from this group suggest a possible relationship between the impairment of carbohydrate metabolism and the type and location of stroke since both the frequency and severity of the hyperglycaemic response were higher in patients with haemorrhagic stroke and brainstem infarction as compared with cerebral infarction. The incidence and degree of the reactive hyperglycaemia were also related to the severity of the acute stroke. There were more comatose patients in the group showing this phenomenon. Initial serum glucose levels in the latter group were higher in unconscious patients than in alert ones. In addition, hospital mortality was significantly higher in these patients. Transitory reactive increases of serum glucose levels were also observed in the majority of patients with a history of overt diabetes prior to the acute stroke. The hyperglycaemic reaction following acute stroke may be attributed to several underlying mechanisms. These include: a non-specific reaction to acute stress and tissue injury with the associated autonomic, hormonal and metabolic alterations; uncovering of underlying latent diabetes by the acute stroke; increased secretion of growth hormone due to stroke-induced hypothalamic dysfunction; and irritation of the glucose regulatory centres in the hypothalamus and brain stem by blood-laden cerebrospinal fluid or local ischaemia.
INTRODUCTION Diabetes mellitus is well established as one of the major risk factors predisposing to cerebrovascular accidents. However, the adverse effect of acute stroke on carbohydrate metabolism is less widely recognized. In experimental animals, acute cerebral
268 ischaemia may be followed by transitory, generalized metabolic abnormalities including marked hyperglycaemia (Wexler and Saroff t970: Wexler 1972). Only limited information is presently available regarding changes in serum glucose tbllowing acute stroke in humans. Occasional studies reported reactive hyperglycaemia in association with subarachnoid haemorrhage (Kecht 1932; Buckell. Richardson and Sarner 1966). Roggia (1957) and Borisenko (1959) reported hyperglycaemia in the acute stage of stroke in series of patients with ischaemic and haemorrhagic cerebrovascular accidents. In the English literature, however, there are practically no studies dealing with this phenomenon in stroke patients, and little attention has been paid to its incidence, severity and duration, relation to the type and location of the acute stroke, and the presence or absence of diabetes prior to the acute event. A retrospective study was therefore undertaken to evaluate the phenomenon of reactive hyperglycaemia following acute stroke in a large series of patients.
MATERIALS AND METHODS The records of patients admitted to the Neurology Department with a diagnosis of acute complete stroke during the period o f January 1969 through October 1975 were surveyed. In all of the patients who were included in the study, the diagnosis was established on the basis of the history, neurological examination, cerebrospinal fluid (CSF) findings, electroencephalographic (EEG) recordings and 99mTc brain scans. Further confirmation of the diagnosis was obtained in some patients by cerebral angiographies and autopsies. According to these data, the patients were classified as suffering from one of the following types of stroke: (t) cerebral infarction; (2) brain-stem infarction (both 1 and 2 were due either to thrombosis or embolism); and (3) haemorrhagic stroke, including intracerebral, intraventricular and subarachnoid haemorrhage (in all of these, blood was demonstrated in the CSF). Excluded from the present study were the following: (1) patients with transient ischaemic attacks; (2) patients who were admitted 24 hr after the onset of their illness; (3) patients in whom the type of stroke was undetermined or uncertain; (4) patients who had an associated, acute major illness at the time of admission, such as myocardial infarction, pulmonary embolism, or an active infectious process; (5) patients to whom steroids were administered before or during their illness; (6) patients in whom the fasting serum glucose level was not determined soon after admission; and (7) patients in whom at least 2 additional daily fasting ~ r u m glucose determinations were not available following initial measurement. Both conscious and unconscious patients were included in the study. Comatose or obtunded patients were given intravenous fluids and/or fed through a naso-gastric tube. Alert patients received regular hospital diet and fluids. Known diabetics received special diet and, unless otherwise indicated, their previous anti-hyperglycaemic treatment was continued unchanged. Stroke patients were considered as overt diabetics prior to stroke if a reliable history of diabetes was obtained from one or more
269 the records of previous hospitalizations or visits to the out-patient clinics of the Hadassah University Hospital. Stroke patients are admitted directly or through the Emergency R o o m to the Neurology Department, usually within the first 24 hr following the acute event. In both cases, a blood sample is routinely drawn for blood urea nitrogen, serum electrolytes and serum glucose determinations immediately upon arrival of the patient and before any food, drink, or intravenous fluids are given. Measurements of fasting serum glucose levels and other biochemical parameters are then repeated daily. In patients receiving intravenous fluids, normal saline is given routinely before the blood sample is drawn. However, since an unknown number of patients might have developed the stroke and reached the department soon after having eaten, the value of the glucose determination performed upon arrival o f the patient may be quest~onable. Therefore, it was decided that the fasting serum glucose level measured on the first morning following admission would be referred to as the initial measurement. Stroke patients were considered to have hyperglycaemia if their fasting serum glucose levels exceeded 120 mg/100 ml. Initial serum glucose levels exceeding 120 mg/100 ml were regarded as reactive hyperglycaemia if. in both diabetic and nondiabetic patients, fasting levels decreased by at [east 20 mg/100 ml on follow-up measurements. During the period January 1969 through October 1975, 392 patients who were admitted with acute completed stroke fulfilled the above criteria and were included in the study. The age range, sex ratio, and relative frequency of the various types of stroke for the total series are presented in Table 1. In 79 (20 ~ of the total series), there was a history of diabetes prior to stroke. Thirty-five patients were on diet only, 39 received oral hypoglycaemic agents, and 5 were on insulin before the acute event.
TABLE 1 AGE, SEX, AND TYPE OF STROKE IN PATIENTS WITH AND WITHOUT REACTIVE HYPERGLYCAEMIA
No. of patients Age (yearS)- mean and range Male/female ratio Type of stroke ( ~ in each group) Cerebral infarction Brain-stem infarction Haemorrhagic stroke
Total series
Group A
Group B
Group C
392
205 (52%)
108 (28~)
79 (20%)
66.7 (45-82) 1.33
66.2 (44-88) 1.38
68.6 (42-90) 1.16
65.2 (48-77) 1.46
71 13 16
80 5 15
56 18 26
70 24 6
A = non-diabetics without reactive hyperglycaemia;B = non-diabeticSwith reactive hyperglycaemia; C = diabetic patients,
270 RESULTS Patients were divided into 3 groups on the basis of a previous history of diabetes and the initial fasting serum glucose level following the acute stroke. Group A included 205 non-diabetic patients (52~o of the total series) in whom the initial serum glucose level was below 120 rag/100 ml. None of these patients had fasting serum glucose levels exceeding 120 mg/100 ml on follow-up measurements. Group B included 108 (28 ~ ) patients who were not known to have diabetes prior to stroke and in whom the initial fasting serum glucose level following admission exceeded 120 rag/100 ml. Group C included 79 (20 ~o) patients with a known history of diabetes prior to stroke. The age range and sex ratio of the three groups are presented in Table 1. There were no differences among the mean ages of the various groups. There were fewer males in Group B and more male diabetics in Group C as compared with the total series and with Group A. The relative frequencies of brain-stem infarction and haemorrhagic stroke were higher, and those of cerebral infarction lower, among Group B patients as compared with Group A (Table 1). The difference in the distribution of the types of stroke between the two groups was significant (P ~< 0.005, chi-squared test). Considering the severity of the hyperglycaemia following the acute stroke in Group B patients, it was observed (Table 2) that the mean initial fasting serum glucose levels were lowest in patients with cerebral infarction, higher in those with brain stem infarction, and highest in those with haemorrhagic stroke. The difference between the mean initial glucose levels of patients with haemorrhagic stroke and those with cerebral infarction was significant (P ~< 0.05, t-test). More patients with brain-stem infarction and haemorrhagic stroke had initial levels of glucose exceeding 200 mg/100 ml as compared with patients suffering from cerebral infarction (Table 2). The severity of the hyperglycaemia was not related to the age and sex of the patients. Insulin was administered to 5 patients (temporarily in survivors), all of whose glucose levers exceeded 300 TABLE 2 INITIAL FASTING SERUM GLUCOSE LEVELS IN NON-DIABETIC PATIENTS WITH REACTIVE HYPERGLYCAEMIA FOLLOWING STROKE (GROUP B) Type of stroke
Total (n 108) Cerebral infarction (n -- 60) Brain-stem infarction (n = 20) Haemorrhagic stroke (n -- 28)
Mean initial serum (mg/100 ml) (mean ± SEM)
IG 121-200 mg/100 ml
1G 201-300 mg/100 ml
IG 301 + rag/100 ml
182 -t- 27
73
22
5
176:~18
84
13
3
188 ~ 24
70
25
5
205~22
54
39
7
IG -- initial fasting serum glucose level.
Percentageof patients
27I mg/100 ml. With respect to the correlation between the level of consciousness and the initial serum glucose levels following the acute stroke, there were more comatose and obtunded patients on admission in G r o u p B (49 ~ ) than in G r o u p A (18 ~ ) . In G r o u p B, the mean initial serum glucose values were higher in the unconscious patients than in the alert ones, 198 ~ 18 and 174 :z 20 mg/100 ml (mean :r: SEM), respectively. The difference was found to be significant (P ~< 0.05, t-test). In all of the G r o u p B patients, the initial hyperglycaemia had been reactive since fasting serum glucose levels decreased by more than 20 mg/t00 ml on follow-up measurements. The decrease in glucose levels followed 3 patterns. In 65 patients (60~o of G r o u p B) with sufficient serial measurements, glucose levels decreased below 120 mg/100 ml (in the majority even below 100 mg/ml). In 11 patients (10~o), glucose levels decreased but remained stabilized above 120 mg/100 ml. In each o f these cases the initial fasting serum glucose exceeded 200 mg/100 ml. In 32 (30~), though glucose levels decreased, there were no sufficient serial determinations to indicate the final outcome of the initial hyperglycaemia, mainly because of early hospital mortality. Serum glucose decreased below or first reached stabilized levels above 120 mg/100 ml following a mean period of 3.7 days (range 2-11 days). In general, the period was longer in patients with higher initial glucose levels. Hospital mortality among G r o u p B patients was 3 times that of G r o u p A (Table 3). The difference was significant (P ~< 0.005, chi-squared test). The differences in mortality rates between the two groups were significant for patients with cerebral infarction and for those with haemorrhagic stroke (P ~< 0.005 and P ~< 0.05. respectively, chi-squared test). It was not significant for patients with brain-stem infarction, perhaps because of the small number of patients with t h a t type o f stroke, In all of the patients with a previous history of diabetes (Group C), the initial fasting serum glucose levels exceeded 120 rag/100 rot. Frequency of types o f stroke TABLE 3 HOSPITAL MORTALITY AMONG STROKE PATIENTS WITH AND WITHOUT REACTIVE HYPERGLYCAEMIA Type of stroke Cerebral infarction No. of patients mortality Brain-stem infarction No. of patients % mortality Haemorrhagic stroke No. of patients mortality Total No. of patients mortality a
Total series
Group A
Group B
Group Ca
279 20
164 12
60 43
40 25
50 46
1l 27
20 60
17 47
63 59
30 43
28 71
5 80
392 30
205 l7
108 54
62 35
Only diabetics with reactive hyperglycaemia are included. There was no mortality among 17 additional diabetics with no reactive hyperglycaemia.
272 in Group C is presented in Table 1. In 21/o°/ of Group C patients (17 patients, 15 with cerebral and 2 with brain-stem infarction), glucose levels did not increase following the acute stroke, since initial and follow-up measurements were essentially the same. Glucose levels in this subgroup did not exceed 200 mg/100 ml, none had been on insulin treatment prior to stroke, all were conscious at the time of admission, and none of these patients died during hospitalization. In 62 diabetic patients (79 °ii of Group C), there was a reactive increase in serum glucose levels following the acute stroke, since levels later decreased by more than 20 mg/100 ml (range 35-225 mg/100 ml) on follow-up measurements. In this subgroup, mean initial glucose levels were higher than those in Group B: 260 ± 29 and 182 ± 27 mg/100 ml (mean ::~ SEM), respectively. There were no significant differences in the mean initial values for the various types of stroke in this subgroup. Mean levels for cerebral infarction, brainstem infarction and haemorrhagic stroke were 271 ± 32, 257 ~+~ 25, and 253 ~ 29 rag/100 ml (mean ~ SEM), respectively. In 22 diabetic patients who had not received insulin prior to stroke, this drug had to be administered (temporarily in all survivors). In all of the 5 patients who had been on insulin prior to the stroke, the daily dosage was temporarily increased (all survived). Age, sex, and level of consciousness on admission did not significantly affect the initial serum glucose levels in this subgroup. In 45 out of the 62 diabetic patients with a reactive increase in glucose levels, there were sufficient serial follow-up glucose measurements. Decreased stabilized glucose values were first achieved following a mean period of 7.8 days (range 4-19 days). Hospital mortality rate among Group C patients with reactive hyperglycaemia was twice that of Group A (Table 3). The difference was significant (P ~< 0.05, chisquared test). The differences in mortality rates between the two groups were significant for patients with cerebral infarction (P ~< 0.01) and not significant for those with brain-stem infarction and haemorrhagic stroke, perhaps because of the small number of patients with these types of stroke. DISCUSSION
The present study shows that a large number of stroke patients without a previous history of diabetes mellitus may develop transitory reactive hyperglycaemia soon after an acute cerebrovascular event. Likewise, transitory reactive elevation of serum glucose levels has been observed in the majority of diabetic stroke patients during the acute period of their illness. The reactive hyperglycaemia is probably not an isolated phenomenon but represents one aspect of the multiple biochemical abnormalities associated with acute stroke (Buckell et al. 1966). It is possible that many factors are capable of affecting carbohydrate metabolism during the period following the acute stroke. The exact mechanism underlying this phenomenon, however, is not clearly understood, and several explanations may be suggested. Reactive hyperglycaemia has been reported following burns (Butterfield 1955) and surgical procedures (Selye 1946). It has also been observed in association with infection, trauma (Kinney, Long and Duke 1970) and acute myocardial infarction (MacKenzie, Taylor, Flenley, McDonald, Staunton and Donald 1969; McDonald,
273 Baker, Bray, McDonald and Restieux 1969). The reactive hyperg!ycaemia observed in the present study may, therefore, be considered as a non-specific reaction. It may merely be one reflection of the multiple autonomic, hormonal and metabolic alterations induced by the acute stress and tissue injury with stroke. Stress, with the resultant release of catecholamines, may induce hyperglycaemia in these patients through blocking of peripheral uptake of glucose, increasing its hepatic release and inhibiting insulin release from the pancreatic fl-cells (Huff and Lebovitz 1968). The existence of such a mechanism may be supported by the observation of increased urinary secretion of catecholammes in patients with acute stroke (Tomomatsu t964: Kawiak and Stelmasiak 1967). Adrenocortical overactivity in reaction to stress and tissue injury may also be a factor in the induction of reactive hyperglycaemia (Ross, Johnston, Welborn and Wright 1966). Though increased serum cortisol levels have been reported following cerebral ischaemia in experimental animals (Wexler 1972) and mildly increased urinary secretion of steroids has been observed in some patients recovering from subarachnoid haemorrhage (Hallpike, Claveria, Cohen and Lasceltes 1971), information concerning adrenocortical hormonal alterations in patients with acute stroke is lacking. In general, elevated glucose levels in acute stroke may be part of a hypercatabolic syndrome which al so includes findings of insulin resistance and marked negative nitrogen balance (Kinney et al. 1970) observed in patients and experimental animals following tissue injury. Data from the present study seem to support a possible role of stress and tissue injury in the induction of serum glucose abnormalities. It may be assumed that the degree of stress and tissue injury is proportional to the severity of the acute cerebrovascular accident. Accordingly, a correlation has been demonstrated between the frequency and severity of reactive hyperglycaemia and the severity of the acute stroke. There were more comatose patients in the non-diabetic group showing reactive hyperglycaemm than in the one not exhibiting this phenomenon. In the former group, significantly higher initial glucose levels were found in comatose patients as compared with the alert ones. In addition, hospital mortality rate. another indicator of stroke severity, was significantly higher among patients with no previous history of diabetes who showed reactive hyperglycaemia. Deterioration of hyperglycaemia in diabetic patients as a reaction to stressful events is a common experience. Thus. in the present study, the majority of patients with a history of diabetes exhibited transitory reactive increases of serum glucose levels. It may be argued that the hyperglycaemic response observed in the group of patients without a history of diabetes prior to stroke might have been due to "uncovering" of either previously unrecognized overt diabetes or of underlying latent diabetes by the acute stress. Return of increased initial serum glucose to stabilized levels exceeding 120 mg/100 ml in some patients in this group may, indeed, serve as evidence of pre-existing overt diabetes in these patients. The possibility that the hyperglycaemic response in the majority of this group reflects on the presence of latent diabetes unmasked by acute stress seems unlikely in view of its existence in a large number of patients in the present study. On the basis of this hypothesis, the number of diabetics would have amounted to 48 ~ of the present stroke series, whereas the
274 reported prevalence of diabetes among stroke patients is much lower (Kurland, Choi and Sayre 1967). Still, such a mechanism may operate in some patients with acute cerebrovascular event. Theoretically, stroke-induced hypothalamic dysfunction may result in increased secretion of growth hormone by the hypophysis. The diabetogenic effect of growth hormone may be a contributory factor to the hyperglycaemic response. Data on the secretion of growth hormone immediately following acute stroke is lacking, but mildly increased levels have been reported during the recovery period in patients with severe cerebrovascular accidents. A possible relationship between impairment of carbohydrate metabolism and the location and type of stroke may be suggested. In earlier animal studies, hyperglycaemia and glycosuria following irritative lesions in specific regions of the brain, mainly in the floor of the fourth ventricle and the hypothalamus were reported (Bernard 1859; Donhoffer and Macleod 1932; Anderson, Rioch and Haymaker 1952: Paton 1957). Conceivably, an infarction within the brain stem, or the presence of blood in the CSF, may induce or enhance the hyperglycaemic response due to their irritative effect upon the glucose regulatory centers. An association of higher frequency and severity of reactive hyperglycaemia in patients with hemorrhagic stroke and brain-stem infarction found in the present study reinforces this theory. It is possible that reactive hyperglycaemia associated with acute stroke in patients with no previous history of diabetes may be attributed to one or more of the above-mentioned factors. Similar mechanisms may also operate in the production of glucose intolerance and insulin resistance reported during the recovery period in patients with subarachnoid haemorrhage (Hallpike et al. 1971) and other types of stroke. Whatever the mechanism, the present data indicate a graver prognosis for acute stroke patients showing the phenomenon of reactive hyperglycaemia. ACKNOWLEDGEMENT The author is grateful to Dr. E. Simchen for her assistance in the statistical analysis of the data.
REFERENCES Anderson, E., D. M. Rioch and W. Haymaker (1952) Disturbances in blood sugar regulation in animals subjected to transection of the brain stem, Aeta Neuroveg., 5:132 164. Bernard, C. (1859) Lecons sur la Physiologie et la Pathologie du SystOme Nerveux, Vol. I. Bailli6re, Paris, pp. 448~462. Borisenko, R. I. (1959) Chemical blood changes in acute disorders of cerebral circulation and their clinical significance, Zh. Nevropat. Psikhiat., 59 : 452-454. Buckell, M., A. Richardson and M. Sarner (1966) Biochemical changes after spontaneous subarachnoid haemorrhage, Part 2 (The patient on admission), J. Neurol. Neurosurg. Psychiat., 29: 293-298. Butterfield, W. J. H. (1955) Hypoglycaemic effect of dimercaprol (BAL) in burned patients and in diabetics with insulin-resistant hyperglycaemia, Lancet, 1: 489-490. Donhoffer, C. and J. J. R. Macleod (1932) Studies in nervous control of carbohydrate metabolism, Part 1 (The position of the centre), Proc. roy. Soc., Ser. B., 110:125 141.
275 Hallpike, J. F., L. E. Claveria. N. M. Cohen and P. T. Lascelles ~1971) Glucose tolerance and plasma insulin levels in subarachnoid haemorrhage, Brain. 94: 151-164. Huff, T. A. and H. E. Lebovitz (1968) Dynamics of insulin secretion in myotonic dystrophy, J. olin. Endocr.. 28: 992-998. Kawiak, W. and Z. Stelmasiak ~1967) Urinary excretion of 3-methoxy-4,hydroxymandetic acid (VMA) in patients after cerebral stroke, Neurol. Neuroehir. Pol.. 1 : 301 307. Kecht. B. (1932) Beitrag zur Frage der cerebralen Hyperglykaemie und ihrer differentialdiagnostischen Bedeutung bei Hirnblutungen. Z. kiln. Med.. 122: 477-489. Kinney, J. M.. C. L. Long and J. H Duke (1970) Carbohydrate and mtrogen metabolism after injury. In: R. Porter and J. Knight (Eds.). Energy Metabolism in Trauma. J. and A. Churchill. London. p. 103. Kurland, L. T.. N. W. Choi and G. P. Sayre (1967) Current status of the epidemiology of cerebrovascular disease in stroke rehabilitation. In: W. S. Fields and W. A. Spencer (Eds.), Stroke Rehabilitation - Basic' Concepts and Research Trends. W. H. Green. Inc.. St. Louis. Missouri. pp. 3-22. McDonald. L.. C. Baker, C. Bray, A. McDonald and N. Restieux tl969) Plasma catecholamines after cardiac infarction. Lancet. 2: 1021-1023. MacKenzie. G. J.. S. H. Taylor. D. C. Flentey, A. H. McDonald. A. H. Staunton and K W. Donald (19641 Circulatory and respiratory studies in myocardial infarction and cardiogenic shock, Lancet. 2: 825-832. Paton, A. (1957) The hypothalamus and carbohydrate regulation. J. Endocr.. 15: 33-39. Roggia, A. t1957) Considerazioni sui rilievi clinico-evolutivo ed ematochimici in 342 casi di apoplessia cerebrale. Minerva Med.. 48 (2): 3305-3308. Ross, H., 1. D. A. Johnston. T. A. Welborn and A D. Wright (1966) Effect of abdominal operation on glucose tolerance and serum levels of insulin, growth hormones, and hydrocortisone, Lancet. 2 : 563-566. Selye, H. (1946) The general adaptation syndrome and the diseases of adaptation, J. clin. Endocr.. 6: t 17-230. Tomomatsu. T. ~1964) ECG observations and urinary excretion of catecholamines in cerebrovascular accidents. Jap. Circ. J.. 28: 905-912. Wexler. B. C. (1972~ Pathophysiotogical responses to acute cerebral ischaemia in the gerbil. Stroke. 3:71 -78. Wexler, B. C. and J. Saroff (1970) Metabolic changes in response to acute cerebral ischaemia following unilateral carotid artery ligation in arteriosclerotic versus nonarteriosclerotic rats. Stroke. I : 38-51.
267
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
REACTIVE H Y P E R G L Y C A E M I A IN PATIENTS W I T H A C U T E S T R O K E
ELDAD MELAMED Department of Neurology, Hadassah University Hospital and Hebrew University - - Hadassah Medical School, Jerusalem (Israel)
(Received 4 February, 1976)
SUMMARY Initial and follow-up fasting serum glucose levels following acute stroke were evaluated retrospectively in 392 selected hospitalized patients. Transitory reactive hyperglycaemia was observed in a large number of patients (28 ~ of the total series) without a history of diabetes prior to the acute cerebrovascular event. The data from this group suggest a possible relationship between the impairment of carbohydrate metabolism and the type and location of stroke since both the frequency and severity of the hyperglycaemic response were higher in patients with haemorrhagic stroke and brainstem infarction as compared with cerebral infarction. The incidence and degree of the reactive hyperglycaemia were also related to the severity of the acute stroke. There were more comatose patients in the group showing this phenomenon. Initial serum glucose levels in the latter group were higher in unconscious patients than in alert ones. In addition, hospital mortality was significantly higher in these patients. Transitory reactive increases of serum glucose levels were also observed in the majority of patients with a history of overt diabetes prior to the acute stroke. The hyperglycaemic reaction following acute stroke may be attributed to several underlying mechanisms. These include: a non-specific reaction to acute stress and tissue injury with the associated autonomic, hormonal and metabolic alterations; uncovering of underlying latent diabetes by the acute stroke; increased secretion of growth hormone due to stroke-induced hypothalamic dysfunction; and irritation of the glucose regulatory centres in the hypothalamus and brain stem by blood-laden cerebrospinal fluid or local ischaemia.
INTRODUCTION Diabetes mellitus is well established as one of the major risk factors predisposing to cerebrovascular accidents. However, the adverse effect of acute stroke on carbohydrate metabolism is less widely recognized. In experimental animals, acute cerebral
268 ischaemia may be followed by transitory, generalized metabolic abnormalities including marked hyperglycaemia (Wexler and Saroff t970: Wexler 1972). Only limited information is presently available regarding changes in serum glucose tbllowing acute stroke in humans. Occasional studies reported reactive hyperglycaemia in association with subarachnoid haemorrhage (Kecht 1932; Buckell. Richardson and Sarner 1966). Roggia (1957) and Borisenko (1959) reported hyperglycaemia in the acute stage of stroke in series of patients with ischaemic and haemorrhagic cerebrovascular accidents. In the English literature, however, there are practically no studies dealing with this phenomenon in stroke patients, and little attention has been paid to its incidence, severity and duration, relation to the type and location of the acute stroke, and the presence or absence of diabetes prior to the acute event. A retrospective study was therefore undertaken to evaluate the phenomenon of reactive hyperglycaemia following acute stroke in a large series of patients.
MATERIALS AND METHODS The records of patients admitted to the Neurology Department with a diagnosis of acute complete stroke during the period o f January 1969 through October 1975 were surveyed. In all of the patients who were included in the study, the diagnosis was established on the basis of the history, neurological examination, cerebrospinal fluid (CSF) findings, electroencephalographic (EEG) recordings and 99mTc brain scans. Further confirmation of the diagnosis was obtained in some patients by cerebral angiographies and autopsies. According to these data, the patients were classified as suffering from one of the following types of stroke: (t) cerebral infarction; (2) brain-stem infarction (both 1 and 2 were due either to thrombosis or embolism); and (3) haemorrhagic stroke, including intracerebral, intraventricular and subarachnoid haemorrhage (in all of these, blood was demonstrated in the CSF). Excluded from the present study were the following: (1) patients with transient ischaemic attacks; (2) patients who were admitted 24 hr after the onset of their illness; (3) patients in whom the type of stroke was undetermined or uncertain; (4) patients who had an associated, acute major illness at the time of admission, such as myocardial infarction, pulmonary embolism, or an active infectious process; (5) patients to whom steroids were administered before or during their illness; (6) patients in whom the fasting serum glucose level was not determined soon after admission; and (7) patients in whom at least 2 additional daily fasting ~ r u m glucose determinations were not available following initial measurement. Both conscious and unconscious patients were included in the study. Comatose or obtunded patients were given intravenous fluids and/or fed through a naso-gastric tube. Alert patients received regular hospital diet and fluids. Known diabetics received special diet and, unless otherwise indicated, their previous anti-hyperglycaemic treatment was continued unchanged. Stroke patients were considered as overt diabetics prior to stroke if a reliable history of diabetes was obtained from one or more
269 the records of previous hospitalizations or visits to the out-patient clinics of the Hadassah University Hospital. Stroke patients are admitted directly or through the Emergency R o o m to the Neurology Department, usually within the first 24 hr following the acute event. In both cases, a blood sample is routinely drawn for blood urea nitrogen, serum electrolytes and serum glucose determinations immediately upon arrival of the patient and before any food, drink, or intravenous fluids are given. Measurements of fasting serum glucose levels and other biochemical parameters are then repeated daily. In patients receiving intravenous fluids, normal saline is given routinely before the blood sample is drawn. However, since an unknown number of patients might have developed the stroke and reached the department soon after having eaten, the value of the glucose determination performed upon arrival o f the patient may be quest~onable. Therefore, it was decided that the fasting serum glucose level measured on the first morning following admission would be referred to as the initial measurement. Stroke patients were considered to have hyperglycaemia if their fasting serum glucose levels exceeded 120 mg/100 ml. Initial serum glucose levels exceeding 120 mg/100 ml were regarded as reactive hyperglycaemia if. in both diabetic and nondiabetic patients, fasting levels decreased by at [east 20 mg/100 ml on follow-up measurements. During the period January 1969 through October 1975, 392 patients who were admitted with acute completed stroke fulfilled the above criteria and were included in the study. The age range, sex ratio, and relative frequency of the various types of stroke for the total series are presented in Table 1. In 79 (20 ~ of the total series), there was a history of diabetes prior to stroke. Thirty-five patients were on diet only, 39 received oral hypoglycaemic agents, and 5 were on insulin before the acute event.
TABLE 1 AGE, SEX, AND TYPE OF STROKE IN PATIENTS WITH AND WITHOUT REACTIVE HYPERGLYCAEMIA
No. of patients Age (yearS)- mean and range Male/female ratio Type of stroke ( ~ in each group) Cerebral infarction Brain-stem infarction Haemorrhagic stroke
Total series
Group A
Group B
Group C
392
205 (52%)
108 (28~)
79 (20%)
66.7 (45-82) 1.33
66.2 (44-88) 1.38
68.6 (42-90) 1.16
65.2 (48-77) 1.46
71 13 16
80 5 15
56 18 26
70 24 6
A = non-diabetics without reactive hyperglycaemia;B = non-diabeticSwith reactive hyperglycaemia; C = diabetic patients,
270 RESULTS Patients were divided into 3 groups on the basis of a previous history of diabetes and the initial fasting serum glucose level following the acute stroke. Group A included 205 non-diabetic patients (52~o of the total series) in whom the initial serum glucose level was below 120 rag/100 ml. None of these patients had fasting serum glucose levels exceeding 120 mg/100 ml on follow-up measurements. Group B included 108 (28 ~ ) patients who were not known to have diabetes prior to stroke and in whom the initial fasting serum glucose level following admission exceeded 120 rag/100 ml. Group C included 79 (20 ~o) patients with a known history of diabetes prior to stroke. The age range and sex ratio of the three groups are presented in Table 1. There were no differences among the mean ages of the various groups. There were fewer males in Group B and more male diabetics in Group C as compared with the total series and with Group A. The relative frequencies of brain-stem infarction and haemorrhagic stroke were higher, and those of cerebral infarction lower, among Group B patients as compared with Group A (Table 1). The difference in the distribution of the types of stroke between the two groups was significant (P ~< 0.005, chi-squared test). Considering the severity of the hyperglycaemia following the acute stroke in Group B patients, it was observed (Table 2) that the mean initial fasting serum glucose levels were lowest in patients with cerebral infarction, higher in those with brain stem infarction, and highest in those with haemorrhagic stroke. The difference between the mean initial glucose levels of patients with haemorrhagic stroke and those with cerebral infarction was significant (P ~< 0.05, t-test). More patients with brain-stem infarction and haemorrhagic stroke had initial levels of glucose exceeding 200 mg/100 ml as compared with patients suffering from cerebral infarction (Table 2). The severity of the hyperglycaemia was not related to the age and sex of the patients. Insulin was administered to 5 patients (temporarily in survivors), all of whose glucose levers exceeded 300 TABLE 2 INITIAL FASTING SERUM GLUCOSE LEVELS IN NON-DIABETIC PATIENTS WITH REACTIVE HYPERGLYCAEMIA FOLLOWING STROKE (GROUP B) Type of stroke
Total (n 108) Cerebral infarction (n -- 60) Brain-stem infarction (n = 20) Haemorrhagic stroke (n -- 28)
Mean initial serum (mg/100 ml) (mean ± SEM)
IG 121-200 mg/100 ml
1G 201-300 mg/100 ml
IG 301 + rag/100 ml
182 -t- 27
73
22
5
176:~18
84
13
3
188 ~ 24
70
25
5
205~22
54
39
7
IG -- initial fasting serum glucose level.
Percentageof patients
27I mg/100 ml. With respect to the correlation between the level of consciousness and the initial serum glucose levels following the acute stroke, there were more comatose and obtunded patients on admission in G r o u p B (49 ~ ) than in G r o u p A (18 ~ ) . In G r o u p B, the mean initial serum glucose values were higher in the unconscious patients than in the alert ones, 198 ~ 18 and 174 :z 20 mg/100 ml (mean :r: SEM), respectively. The difference was found to be significant (P ~< 0.05, t-test). In all of the G r o u p B patients, the initial hyperglycaemia had been reactive since fasting serum glucose levels decreased by more than 20 mg/t00 ml on follow-up measurements. The decrease in glucose levels followed 3 patterns. In 65 patients (60~o of G r o u p B) with sufficient serial measurements, glucose levels decreased below 120 mg/100 ml (in the majority even below 100 mg/ml). In 11 patients (10~o), glucose levels decreased but remained stabilized above 120 mg/100 ml. In each o f these cases the initial fasting serum glucose exceeded 200 mg/100 ml. In 32 (30~), though glucose levels decreased, there were no sufficient serial determinations to indicate the final outcome of the initial hyperglycaemia, mainly because of early hospital mortality. Serum glucose decreased below or first reached stabilized levels above 120 mg/100 ml following a mean period of 3.7 days (range 2-11 days). In general, the period was longer in patients with higher initial glucose levels. Hospital mortality among G r o u p B patients was 3 times that of G r o u p A (Table 3). The difference was significant (P ~< 0.005, chi-squared test). The differences in mortality rates between the two groups were significant for patients with cerebral infarction and for those with haemorrhagic stroke (P ~< 0.005 and P ~< 0.05. respectively, chi-squared test). It was not significant for patients with brain-stem infarction, perhaps because of the small number of patients with t h a t type o f stroke, In all of the patients with a previous history of diabetes (Group C), the initial fasting serum glucose levels exceeded 120 rag/100 rot. Frequency of types o f stroke TABLE 3 HOSPITAL MORTALITY AMONG STROKE PATIENTS WITH AND WITHOUT REACTIVE HYPERGLYCAEMIA Type of stroke Cerebral infarction No. of patients mortality Brain-stem infarction No. of patients % mortality Haemorrhagic stroke No. of patients mortality Total No. of patients mortality a
Total series
Group A
Group B
Group Ca
279 20
164 12
60 43
40 25
50 46
1l 27
20 60
17 47
63 59
30 43
28 71
5 80
392 30
205 l7
108 54
62 35
Only diabetics with reactive hyperglycaemia are included. There was no mortality among 17 additional diabetics with no reactive hyperglycaemia.
272 in Group C is presented in Table 1. In 21/o°/ of Group C patients (17 patients, 15 with cerebral and 2 with brain-stem infarction), glucose levels did not increase following the acute stroke, since initial and follow-up measurements were essentially the same. Glucose levels in this subgroup did not exceed 200 mg/100 ml, none had been on insulin treatment prior to stroke, all were conscious at the time of admission, and none of these patients died during hospitalization. In 62 diabetic patients (79 °ii of Group C), there was a reactive increase in serum glucose levels following the acute stroke, since levels later decreased by more than 20 mg/100 ml (range 35-225 mg/100 ml) on follow-up measurements. In this subgroup, mean initial glucose levels were higher than those in Group B: 260 ± 29 and 182 ± 27 mg/100 ml (mean ::~ SEM), respectively. There were no significant differences in the mean initial values for the various types of stroke in this subgroup. Mean levels for cerebral infarction, brainstem infarction and haemorrhagic stroke were 271 ± 32, 257 ~+~ 25, and 253 ~ 29 rag/100 ml (mean ~ SEM), respectively. In 22 diabetic patients who had not received insulin prior to stroke, this drug had to be administered (temporarily in all survivors). In all of the 5 patients who had been on insulin prior to the stroke, the daily dosage was temporarily increased (all survived). Age, sex, and level of consciousness on admission did not significantly affect the initial serum glucose levels in this subgroup. In 45 out of the 62 diabetic patients with a reactive increase in glucose levels, there were sufficient serial follow-up glucose measurements. Decreased stabilized glucose values were first achieved following a mean period of 7.8 days (range 4-19 days). Hospital mortality rate among Group C patients with reactive hyperglycaemia was twice that of Group A (Table 3). The difference was significant (P ~< 0.05, chisquared test). The differences in mortality rates between the two groups were significant for patients with cerebral infarction (P ~< 0.01) and not significant for those with brain-stem infarction and haemorrhagic stroke, perhaps because of the small number of patients with these types of stroke. DISCUSSION
The present study shows that a large number of stroke patients without a previous history of diabetes mellitus may develop transitory reactive hyperglycaemia soon after an acute cerebrovascular event. Likewise, transitory reactive elevation of serum glucose levels has been observed in the majority of diabetic stroke patients during the acute period of their illness. The reactive hyperglycaemia is probably not an isolated phenomenon but represents one aspect of the multiple biochemical abnormalities associated with acute stroke (Buckell et al. 1966). It is possible that many factors are capable of affecting carbohydrate metabolism during the period following the acute stroke. The exact mechanism underlying this phenomenon, however, is not clearly understood, and several explanations may be suggested. Reactive hyperglycaemia has been reported following burns (Butterfield 1955) and surgical procedures (Selye 1946). It has also been observed in association with infection, trauma (Kinney, Long and Duke 1970) and acute myocardial infarction (MacKenzie, Taylor, Flenley, McDonald, Staunton and Donald 1969; McDonald,
273 Baker, Bray, McDonald and Restieux 1969). The reactive hyperg!ycaemia observed in the present study may, therefore, be considered as a non-specific reaction. It may merely be one reflection of the multiple autonomic, hormonal and metabolic alterations induced by the acute stress and tissue injury with stroke. Stress, with the resultant release of catecholamines, may induce hyperglycaemia in these patients through blocking of peripheral uptake of glucose, increasing its hepatic release and inhibiting insulin release from the pancreatic fl-cells (Huff and Lebovitz 1968). The existence of such a mechanism may be supported by the observation of increased urinary secretion of catecholammes in patients with acute stroke (Tomomatsu t964: Kawiak and Stelmasiak 1967). Adrenocortical overactivity in reaction to stress and tissue injury may also be a factor in the induction of reactive hyperglycaemia (Ross, Johnston, Welborn and Wright 1966). Though increased serum cortisol levels have been reported following cerebral ischaemia in experimental animals (Wexler 1972) and mildly increased urinary secretion of steroids has been observed in some patients recovering from subarachnoid haemorrhage (Hallpike, Claveria, Cohen and Lasceltes 1971), information concerning adrenocortical hormonal alterations in patients with acute stroke is lacking. In general, elevated glucose levels in acute stroke may be part of a hypercatabolic syndrome which al so includes findings of insulin resistance and marked negative nitrogen balance (Kinney et al. 1970) observed in patients and experimental animals following tissue injury. Data from the present study seem to support a possible role of stress and tissue injury in the induction of serum glucose abnormalities. It may be assumed that the degree of stress and tissue injury is proportional to the severity of the acute cerebrovascular accident. Accordingly, a correlation has been demonstrated between the frequency and severity of reactive hyperglycaemia and the severity of the acute stroke. There were more comatose patients in the non-diabetic group showing reactive hyperglycaemm than in the one not exhibiting this phenomenon. In the former group, significantly higher initial glucose levels were found in comatose patients as compared with the alert ones. In addition, hospital mortality rate. another indicator of stroke severity, was significantly higher among patients with no previous history of diabetes who showed reactive hyperglycaemia. Deterioration of hyperglycaemia in diabetic patients as a reaction to stressful events is a common experience. Thus. in the present study, the majority of patients with a history of diabetes exhibited transitory reactive increases of serum glucose levels. It may be argued that the hyperglycaemic response observed in the group of patients without a history of diabetes prior to stroke might have been due to "uncovering" of either previously unrecognized overt diabetes or of underlying latent diabetes by the acute stress. Return of increased initial serum glucose to stabilized levels exceeding 120 mg/100 ml in some patients in this group may, indeed, serve as evidence of pre-existing overt diabetes in these patients. The possibility that the hyperglycaemic response in the majority of this group reflects on the presence of latent diabetes unmasked by acute stress seems unlikely in view of its existence in a large number of patients in the present study. On the basis of this hypothesis, the number of diabetics would have amounted to 48 ~ of the present stroke series, whereas the
274 reported prevalence of diabetes among stroke patients is much lower (Kurland, Choi and Sayre 1967). Still, such a mechanism may operate in some patients with acute cerebrovascular event. Theoretically, stroke-induced hypothalamic dysfunction may result in increased secretion of growth hormone by the hypophysis. The diabetogenic effect of growth hormone may be a contributory factor to the hyperglycaemic response. Data on the secretion of growth hormone immediately following acute stroke is lacking, but mildly increased levels have been reported during the recovery period in patients with severe cerebrovascular accidents. A possible relationship between impairment of carbohydrate metabolism and the location and type of stroke may be suggested. In earlier animal studies, hyperglycaemia and glycosuria following irritative lesions in specific regions of the brain, mainly in the floor of the fourth ventricle and the hypothalamus were reported (Bernard 1859; Donhoffer and Macleod 1932; Anderson, Rioch and Haymaker 1952: Paton 1957). Conceivably, an infarction within the brain stem, or the presence of blood in the CSF, may induce or enhance the hyperglycaemic response due to their irritative effect upon the glucose regulatory centers. An association of higher frequency and severity of reactive hyperglycaemia in patients with hemorrhagic stroke and brain-stem infarction found in the present study reinforces this theory. It is possible that reactive hyperglycaemia associated with acute stroke in patients with no previous history of diabetes may be attributed to one or more of the above-mentioned factors. Similar mechanisms may also operate in the production of glucose intolerance and insulin resistance reported during the recovery period in patients with subarachnoid haemorrhage (Hallpike et al. 1971) and other types of stroke. Whatever the mechanism, the present data indicate a graver prognosis for acute stroke patients showing the phenomenon of reactive hyperglycaemia. ACKNOWLEDGEMENT The author is grateful to Dr. E. Simchen for her assistance in the statistical analysis of the data.
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