- Email: [email protected]
Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol
Hyperosmolality
with Hyponatremia,
by Inappropriate A. AVIRAM,
M.D.,
A.
PFAU,
Administration M.D.,
J. W.
CZACZKES,
PH.D.,
M.D.
Caused
of Mannitol* and T. D. ULLMANN,
M.D.
Jerusalem, Israel Three cases are described in which hypertonic mannitol solutions were given during the early phases of acute renal failure, leading to a severe clinical state of vascular overfilling together with plasma hyperosmolality and hyponatremia. Peritoneal dialysis in one case corrected the overhydration but failed to remove enough of the mannitol and caused an additional increase in plasma osmolality. In this case and in one other less severe case both hyperosmolality and hyponatremia were corrected by hemodialysis. Because of the life-threatening complications associated with the untimely and massive administration of mannitol, which has been described here, this substance should be given only when its diuretic effect can be watched carefully, and its administration should be discontinued if a small trial dose is not followed by an immediate diuretic response. Hyperosmolality caused by mannitol in anuric or oliguric patients can be treated successfully by hemodialysis.
B
ECAUSE
but it was easily controlled. No significant changes in blood pressure were recorded. In order to ensure copious urine flow and thereby to prevent clot formation in the prostatic bed, 2,500
of its diuretic effect, mannitol has been found useful in preventing the progression of incipient renal shutdown to established renal failure both in animal experiments [1,2] and in man [3,4]. Some observers have warned against its administration once renal failure has become established [3,5,6], and in order to avoid the dangers of its application under these conditions various diagnostic criteria have been advocated [5,7]. However, so far no detailed description has been published of the dangerous clinical condition and the unusual laboratory findings which may be caused by administering mannitol too late and in too massive dosage during the course of developing renal shutdown.
ml. of a 10 per cent solution of mannitol in normal saline solution were given intravenously, in addition to 400 ml. of blood and 2,000 ml. of normal saline solution. The urine flow during and immediately after the operation appeared to be adequate. On the following morning, however, the patient excreted only small quantities of blood-stained urine. At this stage acute renal failure was recognized and the administration of fluids was discontinued. During the following hours the patient became confused and dyspneic. He was extremely thirsty and drank approximately 3 L. of fluid. His face was swollen, the eyeballs were sunken, and the tongue and skin were dry. The visible veins were congested and wet crepitant rales were heard over both lungs. Laboratory examination revealed a blood urea of 75 mg. per cent, serum sodium 125 mEq. per L., serum potassium 5.4 mEq. per L. and total carbon dioxide 22 mEq. per L. On the evening of the same day the serum osmolality was 341 mOsm. per kg. water, whereas the serum sodium was 129 mEq. per L. (Table I). The alarming clinical picture was dominated by signs of marked overhydration. Therefore, removal of fluid by peritoneal dialysis seemed to be indicated. During thirty-six hours of dialysis 12 L. of fluid was
CASE REPORTS CASE 1. A fifty-seven year old man (N.Y.) was admitted to the Department of Urology of the Hadassah University Hospital because of massive hematuria caused by benign prostatic hypertrophy. Physical and laboratory examinations did not reveal any significant abnormality of his cardiovascular system; renal function was normal. A retropubic prostatectomy was performed. The course of the operation was uneventful. There was some oozing of blood from the site of the operation
* From the Laboratory of Clinical Research-Renal Unit and the Department of Urology, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel. Manuscript received July 19, 1966. 648
AMERICAN
JOURNAL
OF
MEDICINE
Inappropriate
Mannitol
Administration-_,hirum ?‘ABLE
iVEIC:F, I. L’KISE
OUTPUT
AND
BLOOD
CHEMISTRY
AFTER
Sodium
138
79 -500 x0.000
6
GO
69 750
250 100
67.750
100
_.. 67.500
68.000
155 560 700 1,700 2,900 1,500
ADMINISTRATION
(PATIENT
N.Y.
11s 168 65 188 280 338 370 480 47
Potassium
4
AND
DURING
COURSt
01:
.A(:II‘h
REI.AL
j
Serum Electrolytes (mEq./l.. )
Lrinr O,ltp”t ml./24 hr.)
66,18/65* 1X 65 6,‘19,‘65 6/19:/G 6:21,‘65t 6.22165 6 ‘22/‘65* 6/23 ‘65 24165 6i25’,65 6,27,!65 6: IN/65 7,12,,65
I
MANNITOL
FAILURE
049
t,f al.
Chloride
Crrbon Dioxide
PldS1,l.l Osmolnlily (mOsm.. kg. l-120
98
26
303
125 129 118 119 131 139
54 6.1 6.9 6.4 4.5 5.2
95 90 86 88 95 94
22 19 18 18 27 33
141 136 137 140 133 138
5.2 5.0 6.1 5.2 4.0 3.8
87 82 80 76 96 96
33 35 31 29 22 24
I
Remarks
Preopernrive Operation, followed by mannirol First postoperative day
infusion
of
;4; 346 381 371 336 359
384 310
Peritoneal dialysis, started Peritoneal dialysis, finished Hemcdialysis, started Hemodialysis. finished
Discharge
* Evening. t Noon.
withdrawn and definite clinical improvement was noted. However, laboratory examinations of the serum at the end of the dialysis revealed that the mannitol had not yet been removed to a sufficient degree. This was evident from the fact that the total reducing substances in the plasma, i.e., glucose and mannitol, were more than 500 mg. per cent, whereas glucose alone, as measured by the glucose-oxidase method, was only 152 mg. per cent. The plasma osmolality had increased to 381 mOsm. per kg. water, whereas the serum sodium was 131 mEq. per L. and the blood urea 118 mg. per cent. Hemodialysis was carried out the next day for eight hours with the Kolff Twin-Coil kidney. This treatment resulted in a marked improvement in both the clinical and biochemical states (Table I). Moreover, most of the mannitol had been removed from the extracellular fluid; total reducing substances were 172 mg. per cent, and glucose was 158 mg. per cent. After hemodialysis the patient remained oliguric for another five days, thereafter he went through a polyuric stage and recovered. The creatinine clearance was 57 ml. per minute twenty-one days after the operation, and 91 ml. per minute three months later. CASE 2. A seventy year old man (Z.T.) was operated on because of an aneurysm of the abdominal aorta. The operation was complicated by bleeding and clot formation in the right femoral artery, which necessitated re-exploration. After the second operation the patient excreted only a few milliliters of urine. He was given 2,000 ml. of 10 per cent solution of mannitol in normal saline solution. However, diuresis did not follow. During the night severe pulmonary edema developed, and the patient was treated with morphine, digitalis and aminophyllin. Labora-
v 0 I. .
42,
APRIL
1967
tory examinations on the next morning revealed a blood urea of 190 mg. per cent, serum sodium 125 mEq. per L.; the serum total osmolality was markedly increased, 380 mOsm. per kg. water. Because of the poor general condition of the patient, with hypotension and rapidly developing gangrene of the right leg, hemodialysis seemed to be contraindicated. The patient died on the fifth day after the operation. CASE 3. A sixty-four year old man (D.Z.) received a mismatched blood transfusion during abdominoperineal resection of a tumor of the rectum. He also suffered from chronic lung disease, severe emphysema and bronchiectases. When his urine output on the day after the operation was found to be only 10 ml., he was given an unknown amount of concentrated mannitol solution, together with 1,500 ml. of saline and 1,000 ml. of glucose. No diuretic response to this treatment was observed. On the following morning the patient was confused, thirsty, dyspneic and cyanotic. The neck veins were congested. Laboratory examinations revealed a blood urea of 92 mg. per cent, potassium 4.5 mEq. per L., sodium 127 mEq. per L., osmolality 450 mOsm. per kg. water, pH 7.42, base excess -4 mEq. per L. Hemodialysis was carried to remove mannitol and to correct the overhydration. This treatment was followed by marked clinical improvement and corresponding correction of the serum osmolality and sodium concentration to nearly normal. Another hemodialysis was performed five days later, since the oliguria continued. By this time, however, pneumonia and severe respiratory insufficiency had developed, the patient did not respond to treatment and he died three days after the second hemodialvsis.
650
Inappropriate
Mannitol Administration-hiram
COMMENTS
Mannitol does not penetrate into the interior of the cells, it is slightly, if at all, metabolized, and its only mode of excretion is via the renal glomeruli. When administered after renal failure has become established, as in these cases, mannitol will remain in the extracellular space, and by its potent osmotic activity may lead to serious clinical disturbances. The clinical picture is alarming, comprising signs and symptoms of tissue dehydration, together with overfilling of the vascular bed. The danger of congestive heart failure, which is always imminent in renal shutdown, is enhanced if an already overloaded vascular bed is expanded still more. The laboratory findings are also unusual: plasma osmolality, even if corrected for the osmotic activity of the usually elevated blood urea, is increased due to the presence of mannitol, whereas the overhydration results in lowered concentrations of serum sodium and chloride. This combination of hyperosmolality and hyponatremia, with vascular overfilling, has not been described in other clinical conditions. Hyponatremia may occur after prolonged mannitol diuresis if sodium losses are not replaced [S], but in these cases total osmolality is not increased and circulating volume is reduced. Hyperosmolality has been reported as a complication of the administration of mannitol to a patient with liver cirrhosis and ascites [9]. This was due to the osmotic diuresis caused by the mannitol infusion, with a greater loss of and was accompanied water than sodium, therefore by dehydration and hypernatremia. A similar mechanism is responsible for the
et al.
hyperosmolar nonketoacidotic coma with dehydration which has been described in diabetic patients [ 70,I I], in whom the high glucose content of the blood leads to massive osmotic diuresis. In such cases, the hyperosmolality of the plasma is not accompanied by hyponatremia and vascular overfilling, as was observed in the cases described herein. REFERENCES 1. SAITO, S., SMITH, L. L., SAITO, I. and HINSHAW, D. B. Prevention and treatment of acute renal failure. An experimental study. Am. J. Surg., 110: 192, 1965. 2. HOFFMEISTER,F. S., REGELSON, W. and WILKENS, H. Acute renal failure. Experimental production and prevention. Lab. Invest., 14: 1506, 1965. 3. BARRY, K. G. and MALLOY, J. P. Oliguric renal failure. J.A.M.A., 179: 510, 1962. 4. POWERS,S. R., BOB& A., STEIN, A. and HOSTNIK,W. Prevention of post-operative acute renal failure with mannitol in 100 cases. Surgery, 55: 15, 1964. 5. ELIAHOU,H. E. and BETA, A. The diagnosis of acute renal failure. Nephron, 2: 287, 1965. 6. MERRILL, J. P. The Treatment of Renal Failure, 2nd ed., p. 140. New York & London, 1965. Grune & Stratton. 7. LUKE, R. G., LINTON, A. L., BRIGGO, J. D. and KENNEDY, A. C. Mannitol therapy in acute renal failure. Lancet, 1: 980, 1965. 8. TUNNER, W. S., KISER, W. S. and MANN, PH. Studies on the significance of decreased serum sodium levels following the clinical use of mannitol. J. Ural., 94: 470, 1965 9. GIPSTEIN, R. M. and BOYLE, J. D. Hypernatremia complicating prolonged mannitol diuresis. New England J. Med., 272: 1116, 1965. 10. SAMENT, S. and SCHWARTZ, M. B. Severe diabetic stupor without ketosis. South African M. J., 31: 893, 1957. 11. HALMOS, P. B., NELSON, J. K. and LOWRY, R. C. Hyperosmolar nonketoacidotic coma in diabetes. Lancet, 1: 675, 1966.
AMERICAN
JOURNAL
OF
MEDICINE
with Hyponatremia,
by Inappropriate A. AVIRAM,
M.D.,
A.
PFAU,
Administration M.D.,
J. W.
CZACZKES,
PH.D.,
M.D.
Caused
of Mannitol* and T. D. ULLMANN,
M.D.
Jerusalem, Israel Three cases are described in which hypertonic mannitol solutions were given during the early phases of acute renal failure, leading to a severe clinical state of vascular overfilling together with plasma hyperosmolality and hyponatremia. Peritoneal dialysis in one case corrected the overhydration but failed to remove enough of the mannitol and caused an additional increase in plasma osmolality. In this case and in one other less severe case both hyperosmolality and hyponatremia were corrected by hemodialysis. Because of the life-threatening complications associated with the untimely and massive administration of mannitol, which has been described here, this substance should be given only when its diuretic effect can be watched carefully, and its administration should be discontinued if a small trial dose is not followed by an immediate diuretic response. Hyperosmolality caused by mannitol in anuric or oliguric patients can be treated successfully by hemodialysis.
B
ECAUSE
but it was easily controlled. No significant changes in blood pressure were recorded. In order to ensure copious urine flow and thereby to prevent clot formation in the prostatic bed, 2,500
of its diuretic effect, mannitol has been found useful in preventing the progression of incipient renal shutdown to established renal failure both in animal experiments [1,2] and in man [3,4]. Some observers have warned against its administration once renal failure has become established [3,5,6], and in order to avoid the dangers of its application under these conditions various diagnostic criteria have been advocated [5,7]. However, so far no detailed description has been published of the dangerous clinical condition and the unusual laboratory findings which may be caused by administering mannitol too late and in too massive dosage during the course of developing renal shutdown.
ml. of a 10 per cent solution of mannitol in normal saline solution were given intravenously, in addition to 400 ml. of blood and 2,000 ml. of normal saline solution. The urine flow during and immediately after the operation appeared to be adequate. On the following morning, however, the patient excreted only small quantities of blood-stained urine. At this stage acute renal failure was recognized and the administration of fluids was discontinued. During the following hours the patient became confused and dyspneic. He was extremely thirsty and drank approximately 3 L. of fluid. His face was swollen, the eyeballs were sunken, and the tongue and skin were dry. The visible veins were congested and wet crepitant rales were heard over both lungs. Laboratory examination revealed a blood urea of 75 mg. per cent, serum sodium 125 mEq. per L., serum potassium 5.4 mEq. per L. and total carbon dioxide 22 mEq. per L. On the evening of the same day the serum osmolality was 341 mOsm. per kg. water, whereas the serum sodium was 129 mEq. per L. (Table I). The alarming clinical picture was dominated by signs of marked overhydration. Therefore, removal of fluid by peritoneal dialysis seemed to be indicated. During thirty-six hours of dialysis 12 L. of fluid was
CASE REPORTS CASE 1. A fifty-seven year old man (N.Y.) was admitted to the Department of Urology of the Hadassah University Hospital because of massive hematuria caused by benign prostatic hypertrophy. Physical and laboratory examinations did not reveal any significant abnormality of his cardiovascular system; renal function was normal. A retropubic prostatectomy was performed. The course of the operation was uneventful. There was some oozing of blood from the site of the operation
* From the Laboratory of Clinical Research-Renal Unit and the Department of Urology, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel. Manuscript received July 19, 1966. 648
AMERICAN
JOURNAL
OF
MEDICINE
Inappropriate
Mannitol
Administration-_,hirum ?‘ABLE
iVEIC:F, I. L’KISE
OUTPUT
AND
BLOOD
CHEMISTRY
AFTER
Sodium
138
79 -500 x0.000
6
GO
69 750
250 100
67.750
100
_.. 67.500
68.000
155 560 700 1,700 2,900 1,500
ADMINISTRATION
(PATIENT
N.Y.
11s 168 65 188 280 338 370 480 47
Potassium
4
AND
DURING
COURSt
01:
.A(:II‘h
REI.AL
j
Serum Electrolytes (mEq./l.. )
Lrinr O,ltp”t ml./24 hr.)
66,18/65* 1X 65 6,‘19,‘65 6/19:/G 6:21,‘65t 6.22165 6 ‘22/‘65* 6/23 ‘65 24165 6i25’,65 6,27,!65 6: IN/65 7,12,,65
I
MANNITOL
FAILURE
049
t,f al.
Chloride
Crrbon Dioxide
PldS1,l.l Osmolnlily (mOsm.. kg. l-120
98
26
303
125 129 118 119 131 139
54 6.1 6.9 6.4 4.5 5.2
95 90 86 88 95 94
22 19 18 18 27 33
141 136 137 140 133 138
5.2 5.0 6.1 5.2 4.0 3.8
87 82 80 76 96 96
33 35 31 29 22 24
I
Remarks
Preopernrive Operation, followed by mannirol First postoperative day
infusion
of
;4; 346 381 371 336 359
384 310
Peritoneal dialysis, started Peritoneal dialysis, finished Hemcdialysis, started Hemodialysis. finished
Discharge
* Evening. t Noon.
withdrawn and definite clinical improvement was noted. However, laboratory examinations of the serum at the end of the dialysis revealed that the mannitol had not yet been removed to a sufficient degree. This was evident from the fact that the total reducing substances in the plasma, i.e., glucose and mannitol, were more than 500 mg. per cent, whereas glucose alone, as measured by the glucose-oxidase method, was only 152 mg. per cent. The plasma osmolality had increased to 381 mOsm. per kg. water, whereas the serum sodium was 131 mEq. per L. and the blood urea 118 mg. per cent. Hemodialysis was carried out the next day for eight hours with the Kolff Twin-Coil kidney. This treatment resulted in a marked improvement in both the clinical and biochemical states (Table I). Moreover, most of the mannitol had been removed from the extracellular fluid; total reducing substances were 172 mg. per cent, and glucose was 158 mg. per cent. After hemodialysis the patient remained oliguric for another five days, thereafter he went through a polyuric stage and recovered. The creatinine clearance was 57 ml. per minute twenty-one days after the operation, and 91 ml. per minute three months later. CASE 2. A seventy year old man (Z.T.) was operated on because of an aneurysm of the abdominal aorta. The operation was complicated by bleeding and clot formation in the right femoral artery, which necessitated re-exploration. After the second operation the patient excreted only a few milliliters of urine. He was given 2,000 ml. of 10 per cent solution of mannitol in normal saline solution. However, diuresis did not follow. During the night severe pulmonary edema developed, and the patient was treated with morphine, digitalis and aminophyllin. Labora-
v 0 I. .
42,
APRIL
1967
tory examinations on the next morning revealed a blood urea of 190 mg. per cent, serum sodium 125 mEq. per L.; the serum total osmolality was markedly increased, 380 mOsm. per kg. water. Because of the poor general condition of the patient, with hypotension and rapidly developing gangrene of the right leg, hemodialysis seemed to be contraindicated. The patient died on the fifth day after the operation. CASE 3. A sixty-four year old man (D.Z.) received a mismatched blood transfusion during abdominoperineal resection of a tumor of the rectum. He also suffered from chronic lung disease, severe emphysema and bronchiectases. When his urine output on the day after the operation was found to be only 10 ml., he was given an unknown amount of concentrated mannitol solution, together with 1,500 ml. of saline and 1,000 ml. of glucose. No diuretic response to this treatment was observed. On the following morning the patient was confused, thirsty, dyspneic and cyanotic. The neck veins were congested. Laboratory examinations revealed a blood urea of 92 mg. per cent, potassium 4.5 mEq. per L., sodium 127 mEq. per L., osmolality 450 mOsm. per kg. water, pH 7.42, base excess -4 mEq. per L. Hemodialysis was carried to remove mannitol and to correct the overhydration. This treatment was followed by marked clinical improvement and corresponding correction of the serum osmolality and sodium concentration to nearly normal. Another hemodialysis was performed five days later, since the oliguria continued. By this time, however, pneumonia and severe respiratory insufficiency had developed, the patient did not respond to treatment and he died three days after the second hemodialvsis.
650
Inappropriate
Mannitol Administration-hiram
COMMENTS
Mannitol does not penetrate into the interior of the cells, it is slightly, if at all, metabolized, and its only mode of excretion is via the renal glomeruli. When administered after renal failure has become established, as in these cases, mannitol will remain in the extracellular space, and by its potent osmotic activity may lead to serious clinical disturbances. The clinical picture is alarming, comprising signs and symptoms of tissue dehydration, together with overfilling of the vascular bed. The danger of congestive heart failure, which is always imminent in renal shutdown, is enhanced if an already overloaded vascular bed is expanded still more. The laboratory findings are also unusual: plasma osmolality, even if corrected for the osmotic activity of the usually elevated blood urea, is increased due to the presence of mannitol, whereas the overhydration results in lowered concentrations of serum sodium and chloride. This combination of hyperosmolality and hyponatremia, with vascular overfilling, has not been described in other clinical conditions. Hyponatremia may occur after prolonged mannitol diuresis if sodium losses are not replaced [S], but in these cases total osmolality is not increased and circulating volume is reduced. Hyperosmolality has been reported as a complication of the administration of mannitol to a patient with liver cirrhosis and ascites [9]. This was due to the osmotic diuresis caused by the mannitol infusion, with a greater loss of and was accompanied water than sodium, therefore by dehydration and hypernatremia. A similar mechanism is responsible for the
et al.
hyperosmolar nonketoacidotic coma with dehydration which has been described in diabetic patients [ 70,I I], in whom the high glucose content of the blood leads to massive osmotic diuresis. In such cases, the hyperosmolality of the plasma is not accompanied by hyponatremia and vascular overfilling, as was observed in the cases described herein. REFERENCES 1. SAITO, S., SMITH, L. L., SAITO, I. and HINSHAW, D. B. Prevention and treatment of acute renal failure. An experimental study. Am. J. Surg., 110: 192, 1965. 2. HOFFMEISTER,F. S., REGELSON, W. and WILKENS, H. Acute renal failure. Experimental production and prevention. Lab. Invest., 14: 1506, 1965. 3. BARRY, K. G. and MALLOY, J. P. Oliguric renal failure. J.A.M.A., 179: 510, 1962. 4. POWERS,S. R., BOB& A., STEIN, A. and HOSTNIK,W. Prevention of post-operative acute renal failure with mannitol in 100 cases. Surgery, 55: 15, 1964. 5. ELIAHOU,H. E. and BETA, A. The diagnosis of acute renal failure. Nephron, 2: 287, 1965. 6. MERRILL, J. P. The Treatment of Renal Failure, 2nd ed., p. 140. New York & London, 1965. Grune & Stratton. 7. LUKE, R. G., LINTON, A. L., BRIGGO, J. D. and KENNEDY, A. C. Mannitol therapy in acute renal failure. Lancet, 1: 980, 1965. 8. TUNNER, W. S., KISER, W. S. and MANN, PH. Studies on the significance of decreased serum sodium levels following the clinical use of mannitol. J. Ural., 94: 470, 1965 9. GIPSTEIN, R. M. and BOYLE, J. D. Hypernatremia complicating prolonged mannitol diuresis. New England J. Med., 272: 1116, 1965. 10. SAMENT, S. and SCHWARTZ, M. B. Severe diabetic stupor without ketosis. South African M. J., 31: 893, 1957. 11. HALMOS, P. B., NELSON, J. K. and LOWRY, R. C. Hyperosmolar nonketoacidotic coma in diabetes. Lancet, 1: 675, 1966.
AMERICAN
JOURNAL
OF
MEDICINE