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Diuretics
Domenic A. Sica
Diuretics
21 CARBONIC ANHYDRASE
(SED-14, 669; SEDA-25, 249; SEDA-26, 238; SEDA-27, 22) INHIBITORS
Acetazolamide Fluid balance
Acetazolamide can cause rapid
volume changes. 9 A47-year-old woman with diabetes who took acetazolamide (250 mg bd for 6-days) for left cystoid macular edema developed profound hyperosmolar non-ketotic hyperglycemia (1A). This occurred as the result of marked diuresis and an associated fall in glomerular filtration rate.
Hematologic
Acetazolamide can cause rapid hematological changes, including thrombocy-
topenia. 9 A67-year-old man developed isolated thrombo-
cytopenia (platelet count 31 • 109/1) after taking acetazolamide 250/mg day for 2 days for raised intraocular pressure (2A). Several months later acetazolamide 375 mg/day was prescribed again and 2 weeks later he developed extensive purpura and a platelet count of 3 • 109/1. Acetazolamide was withdrawn and the platelet count rose spontaneously to 20, 73, and 246 • 109/1 after 1, 3, and 10 days respectively.
Dorzolamide Sensory systems Eyes that have not undergone surgery have not been reported to undergo choroidal detachment with topical hypotensive agents. 9 A76-year-old woman with a 7-year history of open-angle glaucoma presented with distorted visual acuity after applying two doses of dorzolamide eye-drops 2% bd to both eyes (3A). Other 92005 Published by Elsevier B.V.
SideEffectsof Drugs, Annual 28
J.K. Aronson, ed.
systemic medications included hydrochlorothiazide and verapamil. There was a peripheral choroidal detachment in the left eye, which completely resolved 1 week after withdrawal of dorzolamide together with topical glucocorticoid therapy. In this case, the systemic hydrochlorothiazide may have sensitized the choroidal epithelium sufficiently to result in aqueous fluid shutdown.
THIAZIDE AND LOOP
(SED-14, 656; SEDA-25, 252; SEDA-26, 239; SEDA-27, 220)
DIURETICS
Thiazides Musculoskeletal
In a nested case-control study in patients with type 2 diabetes there were 26 cases of a first leg amputation among 12 140 cases. Subjects who used thiazide diuretics alone or together with other antihypertensive medications had a higher risk of leg amputation (crude odds ratio = 6.11) compared with subjects taking ACE inhibitor monotherapy. Thiazide diuretics were also associated with an increased risk of leg amputation than non-thiazide antihypertensive drugs (adjusted odds ratio = 7.04). These findings suggest that thiazide-type diuretics be used cautiously in patients with type 2 diabetes particularly when there is significant lower limb peripheral vascular disease (4c).
Furosemide Hearing loss is a significant problem in survivors in neonatal intensive care units and has been attributed to underlying disease processes and/or exposure to ototoxic drugs, including furosemide. A retrospective chart review (July 2000 to January Sensory systems
233
234 2002) of all survivors in a neonatal intensive care unit was undertaken to evaluate the effect of furosemide on hearing loss (5M). Of the 57 neonates who had received furosemide nine had a subsequent abnormal heating screen, and of the 207 neonates who had not received furosemide 33 also had an abnormal hearing screen. This suggests that hearing loss in these neonates is not directly related to the use of furosemide.
Nutrition
Furosemide has been associated with thiamine deficiency in patients with heart failure. Erythrocyte transketolase activity suggested severe thiamine deficiency in 24 of 25 patients with heart failure who were taking at least 80 mg/day of furosemide and in four of seven patients who were taking 40 rag/day (OR = 19; CI = 1.1,601) (6c). Thiamine status was not associated with any other clinical variables. These findings suggest that thiamine deficiency occurs in a substantial proportion of patients with heart failure who are taking furosemide; however, this is of unclear cfinical significance.
Salivary glands Diuretics cause altered salivary flow rate and composition and have been associated with both subjective and objective evidence of xerostomia. In a randomized trial in 12 healthy women randomly assignment to placebo, bendroflumethiazide (2.5 rag/day for 7 days) and furosemide (40 mg/day for 7 days), xerostomia increased with furosemide in conjunction with a reduction in submandibularsublingual salivary secretion (7c). This was particularly so at lunchtime. This suggests that diuretics may potentiate dryness of the mouth and should be used carefully in patients with abnormal salivary flow.
Urinary tract A 900-gram girl born before term with bronchopulmonary dysplasia developed ureteral obstruction, urinoma, and acute renal insufficiency as a result of furosemiderelated hypercalciuria (cumulative dose 27.5 mg) and nephrolithiasis (8A). Percutaneous drainage of the urinoma plus conversion to hydrochlorothiazide resolved the urinoma and hydronephrosis. Acute renal insufficiency carries a high mortality and morbidity. Diuretics may increase mortality in patients with acute renal insufficiency (SEDA-27, 221), but this has not been
Chapter 21
Domenic A. Sica
studied prospectively. In a prospective, multicenter, multinational, epidemiological study of 1743 consecutive patients, who were either treated with renal replacement therapy or who fulfilled predefined criteria for acute renal insufficiency, about 70% were taking diuretics at enrolment (9M). Severe sepsis/septic shock (48%), major surgery (39%), low cardiac output (30%), and hypovolemia (28%) were the most common conditions associated with the development of acute renal insufficiency. Furosemide was the most common diuretic used (98%). In all three multivariate models, diuretic use was not associated with a significantly increased risk of mortality. The use of diuretics in patients with acute renal insufficiency should continue, but only according to a specific need to control volume excess.
Immunologic
Furosemide rarely causes type 1 allergic reactions. A 24-year-old woman took one tablet of furosernide 40 mg and 10 minutes later developed oral itching, generalized urticaria, facial angioedema, dyspnea, and hypotension (10A). She recovered after the administration of parenteral adrenaline, methylprednisolone, and diphenhydramine. A furosemide skin prick test 10 mg/ml was negative. An intraderreal skin test was positive for furosemide 1% and sulfamethoxazole 0.03 mg/ml.
IgE-mediated reactions to furosemide are infrequent, but can be life-threatening. The positive intradermal test to sulfamethoxazole in this case raises the question of cross-reactivity between non-aromatic and antimicrobial sulfonamides. There is little clinical or pharmacological evidence that a self-reported sulfa allergy is likely to be associated with a life-threatening crossreaction with acetazolamide or furosemide (11 M, 12M). Most patients who report sulfa allergy have actually had an adverse reaction to a sulfonamide antimicrobial drug. There are significant structural differences between sulfonamide antibiotics and other sulfonamide non-antimicrobial drugs such as furosemide and acetazolamide, and generally cross-reactivity would not be expected. In a retrospective cohort study using the General Practice Research Base in the UK, 969 cases with a so-called allergic reaction to an antimicrobial sulfonamide were reviewed (12M).
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Chapter21
Only 96 (9.9%) had an allergic reaction after receiving a non-antimicrobial sulfonamide. Of 19 257 who had no allergic reaction after a antimicrobial sulfonamide, 315 (1.6%) had an allergic reaction However, the risk of allergic reactions was even greater after the use of a penicillin among patients with a prior hypersensitivity reaction to a antimicrobial sulfonamide, compared with patients with no such history (adjusted odds ratio = 3.9) after receiving a non-antimicrobial sulfonamide (adjusted odds ratio = 2.8). In addition, among those with a prior hypersensitivity reaction after an antimicrobial sulfonamide, the risk of an allergic reaction after the subsequent receipt of a nonantimicrobial sulfonamide was lower than the risk of an allergic reaction with penicillin (adjusted odds ratio = 0.7). Finally, the risk of an allergic reaction after an antimicrobial sulfonamide was lower among patients with a history of hypersensitivity to an antimicrobial sulfonamide than among patients with a history of hypersensitivity to penicillins (adjusted odds ratio = 0.6). These results suggest that there is an association between hypersensitivity after an antimicrobial sulfonamide and a subsequent allergic reaction after a non-antimicrobial sulfonamide, but this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.
Drug interactions
Of 10 615 elderly patients continuously taking lithium for over 10 years, 413 (3.9%) were admitted to the hospital at least once with lithium toxicity. After adjustment for potential confounders, there was a 5.5-fold increase in the relative risk of lithium toxicity within 1 month of starting therapy with a loop diuretic (13c). Thiazide diuretics were not independently associated with an increased risk of hospitalization for lithium toxicity. This population-based nested case-control study stresses the importance of monitoring for lithium toxicity whenever a loop diuretic is started.
235
ALDOSTERONE
RECEPTOR
(SED-14,674; SEDA-25, 254; SEDA-240; SEDA-27, 221) ANTAGONISTS
Eplerenone Electrolyte balance HyperkaIemia is always a consideration with spironolactone and eplerenone, but the relation between a beneficial response to eplerenone and the change in serum potassium concentration has been poorly characterized. In 397 hypertensive patients (responders and non-responders) taking eplerenone 50200 mg/day without other susceptibility factors for hyperkalemia, eplerenone caused an increase in serum potassium concentration of 0.2 mmol/1 (14c). The blood pressure lowering effect of eplerenone did not correlate with the change in serum potassium concentration. This suggests that in patients with uncomplicated hypertension, eplerenone can be used without a significant risk of hyperkalemia.
Spironolactone U r i n a r y t r a c t Of 226 patients with heart failure in a retrospective analysis, 25 stopped therapy because of renal dysfunction, 13 primarily because of hyperkalemia and 12 primarily because of a rising creatinine (15c). The mean baseline creatinine in the latter was 140 ~tmol/1, rising to a mean of 197 kLmol/1 at the time of stopping therapy. Eight of 11 patients had a serum creatinine over 200 ~tmol/1. Spironolactone should be considered as one of the several pharmacological factors that can cause deterioration of renal function in heart failure. Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been attributed to spironolactone. 9 A58-year-old man developed erythroderma, fever, anorexia, peripheral edema, eosinophilia, and multi-organ failure while taking several drugs, including spironolactone (16A). All the medications were stopped and the condition completely remitted over 4 months. Patch testing was positive for spironolactone.
236
OSMOTIC DIURETICS (SED-14, 1162, 1236)
Mannitol
Uses of mannitol The number o f uses o f mannitol continues to increase.
Reducing raised intracranial pressure
The use o f mannitol in the treatment o f raised intracraniat pressure has been reviewed, in the light o f disagreements about the appropriate timing o f administration, the optimal fluid management protocol, and the mechanisms of action o f osmotic diuretics (17R-19R ). The effects o f four methods o f infusion o f mannitol and glycerol on raised intracranial pressure, as monitored by epidural pressure recordings, have been studied in 65 patients (20c). A. mannitol 0.5 g/kg was infused over 15, 30, or 60 minutes; B. mannitol 1.0 g/kg was infused over 30, 60, or 90 minutes; C. glycerol 0.5 g/kg in 5%fructose was infused over 30, 60, or 90 minutes; D. glycerol 1.0 g/kg was infused over 60, 120, or 180 minutes. In group A, there were no differences in the reduction in intracranial pressure across the three infusion rates. In group B, the degree o f reduction in intracranial pressure increased with shorter times o f infusion. In groups C and D the reduction in intracraniaI pressure was inversely related to the rate o f infusion. In each group, the slower the infusion rate o f the same dosage, the longer the reduction in intracranial pressure lasted. There was a rebound increase in intracranial pressure in 12% o f those given mannitol and 34% o f those given glycerol The dose and the rate o f mannitol infusion did not affect the rebound. In 22 patients with meningoencephalitis and hypertensive cranial syndrome from cerebral edema, mannitol was given to 13 and dexamethasone to nine (21c). There were three therapeutic failures in those given mannitol and none in those given dexamethasone, although the two
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Domenic A. Sica
drugs had similar effects on the duration o f the hypertensive cranial syndrome (39--44 hours). The patients who were treated with mannitol had hyponatremia after 48 hours. In 43 patients, osmotherapy with mannitol 20% and sorbito140% increased the serum concentration o f lactate but not pyruvate, causing an increased ratio o f lactate to pyruvate (22c). Sorbitol had the greater effect, with a maximum at 1 hour. Mannitol had its maximum effect at 4 hours. The author concluded that acidosis, shock, diabetes mellitus, and hepatic dysfunctions increase the risk o f osmotherapy, especially with sorbitol. Randomized trials o f mannitol in patients with acute traumatic brain injury of any severity have been reviewed (23M). In the preoperative management o f patients with acute intracranial hemorrhage high-dose mannitol reduced mortality (RR = 0.55; 95% CI = 0.36, 0.84) and reduced death and severe disability (RR = 0.58; 95% CI = 0.45, 0.74) compared with conventional-dose mannitol. In one trial treatment intended to lower intracranial pressure was compared with "standard care" (RR f o r death = 0.83; 95% CI = 0.47, 1.46). In one trial mannitol and pentobarbital were compared (RR f o r death = 0.85; 95% CI = 0.52, 1.38). In one trial pre-hospital mannitol was compared with placebo (RR for death = 1.75; 95% CI = 0.48, 6.38). The reviewers concluded that high-dose mannitol is preferable to conventional-dose mannitol in the pre-operative management o f patients with acute intracranial hematomas. However, there is little evidence about the use o f mannitol as a continuous infusion in patients with raised intracranial pressure who do not have an operable intracraniaI hematoma. In 20 patients with head trauma and persistent coma who required infusions o f an osmotic agent to treat episodes o f intracranial hypertension resistant to standard modes o f therapy, isovolumic infusions o f either 7.5% hypertonic saline reduced the number o f episodes o f intracranial hypertension per day (6.9 versus 13.3) and the daily duration o f episodes of intracranial hypertension (67 versus 131 minutes) compared with 20% mannitol (24c). Stroke In 805 patients who were given intravenous mannitol (mean dose, 47 g/day; mean duration, 6 days) or no treatment within 72
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Chapter 21
hours of the onset of a stroke, the case fatality was 25% versus 16% at 30 days and 38% versus 25% at 1 year (25c). The prognostic scores on the Scandinavian Neurological Stroke Scale were similar in treated and untreated patients, both in ischemic and hemorrhagic strokes. However, the patient groups differed in several factors that might have affected survival. Thus, this uncontrolled study was inconclusive. Serum and cerebrospinal fluid osmolarity were measured in 30 patients with severe head injuries or subarachnoid hemorrhage, 10 of whom received mannitol for at least 72 hours, 10 of whom received it for 24-48 hours, and 10 of whom were controls (26c). Serum osmolarity increased quickly in all those who received mannitol and was unchanged in controls. Average cerebrospinal fluid osmolarity increased slowly in all those who received mannitol and was unchanged in controls. This is a potentially dangerous effect and the authors recommended that cerebrospinal fluid osmoIarity should be measured regularly in all patients who receive mannitol for longer than 24 hours. Disrupting the blood-brain barrier Mannitol has been used to disrupt the blood-brain barrier temporarily in order to allow better penetration of chemotherapeutic drugs. In eight patients with gliomas and one with a primary lymphoma of the central nervous system the blood-brain or blood-tumor barrier was reversibly opened by intra-arterial injection of hyperosmolar mannitol 25% (27c). There was tumor regression or a tumor progression-free interval in five patients. In 10 patients with malignant gliomas intraarterial chemotherapy with 5-fluorouracil, nitrosourea, or interferon beta was given after osmotic blood-brain barrier disruption with intraarterial 20% mannitol (28c). In nine evaluable cases there were one complete and three partial responses; in five there was no change and no progressive disease on CT. The most untoward effect was myelosuppression: platelet and leukocyte counts fell below 20 • 109/I and 2 • 109/1 respectively in threepatients, of whom two died of severe infections. The other complications were eye pain during mannitol infusion in all cases in which selective catheterization of the internal carotid artery failed to pass the origin of the ophthalmic artery. There was reduced activity in 70%, nausea and vomiting
237
in 50%, swelling of the external decompression area in 33%, and increased neurological deficits in 20%. However, all these adverse effects were transient. Of 21 patients with malignant brain tumors, 16 were treated by operation, irradiation, and two or more courses of intracarotid infusion of nitrosourea 100 mg after 20% mannito1200 ml, and five were treated similarly but without mannitol (29c). The 2-year survival rate in those who received mannitol was 79% (11 of 14 cases followed for longer than 2 years) and the 3-year survival rate was 67%. Five of seven patients with grade 4 astrocytomas survived for more than 18 months, whereas four of five patients with grade 4 astrocytomas who did not receive mannitol died within 18 months. Over 4 years, 37 patients with high-grade malignant gliomas underwent 246 treatment procedures with a combination of methotrexate, cyclophosphamide, and procarbazine given together with hyperosmolar mannitol-induced transient breakdown of the blood-brain barrier (30~). There were complete remissions in 16% and 24 patients (65%) had partial or temporary remissions. Progression-free intervals were 147 (mean 15) months and median survival was 22 months. Neurotoxicity was minimal with one periprocedural death and five instances of worsened neurological deficits after a procedure. The delivery of chemotherapeutic agents in the treatment of malignant brain tumors is improved by osmotic opening of the bloodbrain barrier by prior infusion of mannitol into the internal carotid or vertebral artery. Over 4200 blood-brain barrier disruption procedures have been performed in over 400 patients with primary central nervous system lymphomas, gliomas, primitive neuroectoderreal tumors, germ cell and metastatic cancers in the National Blood-Brain Barrier Program (31c). In patients with primary nervous system lymphomas, long-lasting responses have been obtained without loss of cognitive function and without the use of radiotherapy. The results in patients with primitive neuroectodermal tumors and germ cell tumors are also said to be very encouraging. The efficacy of mannitol in augmenting the tumoricidal effect of etoposide has been studied in 99 children aged 1-21 years with recurrent brain tumors (32c). They were randomly
238 assigned to intravenous etoposide 150 mg/m 2 with or without mannitol 15 g/m 2, daily for 5 days every 3 weeks for 1 year or until disease progression or death. CT or MRI scans, obtained after three cycles of therapy, were compared with pre-therapy scans. 0 f 8 7 evaluable patients, 12 had an objective response according to the radiologist and of 66 patients reviewed centrally, seven responded (two of 12 low grade astrocytomas, four of 26 medulloblastomas or primitive neuroectodermal tumors, one of 13 high-grade astrocytomas, and one of 15 brain stem gliomas). Survival at 1 year was 53% for low grade astrocytomas, 38% for medulloblastomas or primitive neuroectodermal tumors, 28% for high-grade astrocytomas and 9% for brain stem gliomas. Mannitol had no beneficial effect. Use in bowel cleansing Mannitol has been used for preoperative bowel cleansing before radiological investigations (33c), diagnostic and operative endoscopy (34c), and bowel surgery. In whole gut irrigation mannitol is badly tolerated and leaves a bowel full of gas and fluid although it causes only small changes in serum electrolytes (35R). In a study of the effect of an intravenous infusion of saline on the volume of rectal effluent and quality of bowel preparation produced by a smaller oral dose of mannitol, 19patients drank 2-3 1 of 5% mannitol, supplemented by an intravenous infusion of isotonic saline and 19 patients drank 4-5 1 of 5% mannitol (36c). The volume of rectal effluent and the quality of bowel preparation was the same in both groups. Loss of sodium in the oral group was corrected by the intravenous infusion, but the infusion resulted in greater water retention. There was no difference in the incidence of vomiting between the two groups. Polyethylene glycol electrolyte lavage solution has been compared with 10% mannitol for preoperative colonic cleansing in 80 patients (37c). Colonic cleansing was better with polyethylene glycol (90% optimal cleansing versus 75%). Mannitol caused subclinical dehydration according to hematological, biochemical, and weight changes before and after bowel preparation and caused more nausea, cramps, and abdominal pain. Two patients given mannitol had combustible amounts of hydrogen gas in the colon.
Chapter 21
Domenic A. Sica
Three formulations, two based on magnesium citrate and one an optimized oral mannitol regimen, have been compared for their effectiveness in clearing the large bowel before double-contrast barium enema and for effects on barium mucosal coating (38c). The formulations based on magnesium citrate were equally good and caused significantly less nausea and vomiting than mannitol. The authors concluded that mannitol should not be used for preparing the bowel for barium enema. Two hypotonic non-hemolysing irrigating solutions, sorbitol + mannitol (2% + 1%) and glycine (1.5%), have been compared in patients undergoing transurethral resection of the prostate (39c). Ethanol (1%) was added to the irrigating f u i d as a marker to allow early detection of fluid absorption by breath analysis. There was very little absorption (less than 1 1). However, in other cases large volumes of fluid have been absorbed. In 39 patients having transurethral resection of the prostate for benign prostatic hyperplasia, large quantities of mannitol, which was used as the irrigating fuid, entered the circulation (40c). There was a corresponding fall in serum sodium concentration. Patients who had serum mannitol concentrations over 4 mg/ml had hypotension and bradycardia; because they were nearly all hypovolemic, the bradycardia was thought to be inappropriate. Irrigating fluid bags containing mannitol 3% or glycine 1.5%, both with added ethanol 1% as an indicator of fluid absorption, were used to investigate adverse effects in a randomized, double-blind study during 394 transurethraI prostatic resections (41c). The incidence of 13 symptoms was studied in 52 patients (13%) who absorbed more than 500 ml of fluid. The incidence of circulatory symptoms did not differ between the fluids, but the risk of neurological symptoms, such as nausea, was 4.8 times higher with glycine 1.5%. An increase of 1000 ml in the volume of irrigant absorbed increased the overall risk of circulatory symptoms by a factor of 3.4 and the risk of neurological symptoms by a factor of 4.4. The authors concluded that absorption of mannitol 3% during transurethral prostatic resection is associated with fewer neurological symptoms than glycine 1.5%. In 80 patients randomized for precolonoscopic cleansing with either 10% mannitol 750
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Chapter 21
ml or sodium phosphate 180 ml there were statistically significant differences in serum sodium, phosphorus, potassium, and calcium between the two groups, but no clinical symptoms and no significant differences in the frequencies o f adverse effects (42c). Six o f eight patients who were treated with sodium phosphate and who had mannitol f o r a previous colonoscopy preferred sodium phosphate. The endoscopists, who were blinded to the treatment, reported excellent or good bowel preparation in 85% o f those prepared with sodium phosphate versus 83% f o r mannitol. The authors concluded that although the quality o f preparation and the frequencies o f adverse effects were similar with the two solutions, retention o f sodium and phosphate ions contraindicates the use o f sodium phosphate in patients with renal insufficiency, cirrhosis, ascites, and heart failure. In a retrospective study o f patients who underwent elective surgery f o r colorectal carcinomas, traditional bowel preparation was performed the day before the operation either with oral castor oil 30 ml and three soap enemas (n = 154) or with mannitol 500 ml (n = 36) (43c). There were infectious wound complications in 26 patients (17%) pretreated with castor oil compared with 13 patients (36%) treated with mannitol. There were no differences in the incidence o f anastomotic leaks or mortality rate. Systemic antimicrobial prophylaxis with metronidazole and gentamicin has been compared with metronidazole alone in elective colorectal surgery in a prospective randomized trial in which all the patients received 10% mannitol solution before surgery (44c). Although there were no serious infections in either group, the incidence o f superficial wound infections was relatively high: 19% in those given metronidazole and gentamicin prophylaxis and 25% in those given metronidazole alone. Escherichia coIi was isolated from all these wounds, and no obligate anerobic bacteria were cultured. The high rate o f wound infection was probably caused by overgrowth after irrigation, due to residues o f mannitoI in the colon, which serve as a nutrient f o r Escherichia coli. Both sets o f authors concluded that mannitol should not be used f o r preoperative mechanical preparation o f the large bowel before elective colorectaI surgery.
239 Hydrogen gas can accumulate in the colon after the administration o f mannitol (37c). This can cause a risk o f explosion. 9 Colonic explosion during colonoscopic polypectomy occurred after mannitol had been used for bowel preparation and the colon was completely clean (45A). In spite of emergency surgery, with transfusion of 45 units of blood, uncontrollable hemorrhage persisted from multiple bleeding points and the patient died.
Use as a radiocontrast medium
In 56patients undergoing abdominal CT the gastrointestinal tract was defined by negative contrast with 2.5% mannitol instead o f the conventional positive contrast from an iodine-containing contrast medium (46c). The number o f artifacts due to high-contrast boundaries was slightly greater with negative contrast than it would have been with positive contrast, but differentiation o f the gastrointestinal tract from other abdominal organs was equally good. Negative contrast was poor f o r diagnosing cystic tumors but much better than positive contrast f o r evaluating the wall o f the gastrointestinal tract. The effect o f oral mannitol in an aqueous solution in enhancing pelvic MRI has been reported in a retrospective study in 72 patients with suspected or proven pelvic abnormalities: In 36 patients bowel marking was not carried out and in 36 patients the bowel was contrast-enhanced by oral mannitol 1000 ml (47r Mannitol significantly improved delineation o f the intestinal structures and pelvic organs or pathological lesions, but eight patients had diarrhea, nausea, or meteorism.
Diagnosis of diarrhea In chronic diarrhea intestinal permeability to sugars, such as raffinose, lactose, lactulose, sucrose and mannitol (48c), can detect intestinal damage. The absorption o f a combined dose o f lactulose and mannitol has been studied in 261 consecutive patients with three or more bowel movements daily f o r at least 3 weeks; 120 (46%) were found to have an organic cause f o r chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed (49c). The lactulose/mannitol test and C-reactive protein were independent predictors f o r the final diagnosis o f an organic cause o f chronic diarrhea, with odds ratios o f l.5 (95% CI = 1.29, 1.78) and 5.2 (95% CI = 1.90, 14.12) respectively.
240 Cardiopulmonary bypass The effects of mannitol and dopamine, alone and in combination, on beta2-microgIobulin excretion rates in 100 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass have been studied in a double-blind, randomized, placebo-controlled study (50c). Mannitol 1 g/kg was added to the cardiopulmonary bypass prime and dopamine 2 micrograms/kg/minute was given from the time of induction of anesthesia to 1 hour after bypass. Dopamine significantly increased the excretion rate of beta2-microglobulin compared with placebo. Thus, rather than being protective during cardiopulmonary bypass, dopamine reduces renal tubular dysfunction. This effect was not ameliorated by the addition of mannitol. Treatment of cisplatin nephrotoxieity Saline alone, saline + furosemide, and saline + mannitol have been used to prevent nephrotoxicity in 49 women who received cisplatin 75 mg/m2 every 3 weeks (51c). Hydration with saline or saline + furosemide was associated with less cisplatin nephrotoxicity than hydration with saline + mannitol. Equiosmolar loads of mannitol 20% and hypertonic saline 7.5% over 10 minutes have been compared with isotonic saline in 30 ASA I and II patients undergoing non-hemorrhagic surgery under general anesthesia (52c). The serum sodium concentration was lowest after mannitol (129 mmol/l) at the end of the infusion and highest after hypertonic saline (151 mmol/1), with normalization at 60 minutes. The hemodynamic effects were similar in the three groups. Temperature was lower after isotonic saline, because of the volume infused. Cardiovascular Glycine (1% or 1.5%) 15 ml/kg, or 3% mannitol (all containing 1% ethanol), or sorbitol 2% + mannitol 1% (with no ethanol) were infused intravenously over 20 minutes into 10 healthy men to determine their hemodynamic effects using Doppler ultrasonography (53c). All reduced cardiac output 30 minutes after infusion, and glycine reduced the heart rate and cardiac output and raised mean arterial pressure, indicating an increase in systemic resistance. Almost identical breathethanol curves were obtained with the three
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fluids containing ethanol and all of them caused slight hypoglycemia. There was no evidence of ethanol-induced tachycardia. Respiratory Inhaled mannitol increases airway responsiveness in asthmatic subjects (54 c) and may act through mast cell activation (55c). It has been used to investigate the effects of therapeutic drugs or to predict responsiveness to their effects and to determine susceptibility to exercise-induced bronchoconstriction (56c). In 18 asthmatic subjects the inhaled glucocorticoid budesonide caused a reduction in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms (57c).
Sensory systems The effects of intravenous mannitol on aqueous fluid protein concentration have been evaluated in healthy young adults (average age 20 years) and older adults (average age 61 years), and in patients with diabetes mellitus, hypertension, or pseudoexfoliation syndrome who were about to undergo intraocular surgery (average age 66 years) (58c). Mannitol increased aqueous humor protein concentration in all subjects, with a maximum effects at around 1 hour. The magnitude and the duration of the effect were significantly greater in the healthy older subjects than in the young subjects, but the same in older adults with and without diseases. The effect was reversed within 6 hours. Urinary tract Four cases of acute renal insufficiency have been described in a series of men aged 20--42 years who received mannitol 1172 (SD 439) g over 58 (28) hours (59A). The onset of acute renal insufficiency was detected 48 (22) hours after the start of infusion. All the patients had dilutional hyponatremia (average 120 mmol/l), and serum hyperosmolality (osmolar gap 70 mosm/kg water). In the three patients with anuria, in whom hemodialysis was performed, there was immediate recovery of diuresis. This emphasizes the risk of renal insufficiency with mannitol and stresses the importance of early hemodialysis. Mannitol is dialysable, and functional recovery is prompt once its suppressive effect on renal perfusion is eliminated.
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Chapter21
M u s c u l o s k e l e t a l Mannitol can cause a compartment syndrome if it extravasates into soft tissues (60 A, 61A). 9 A17-year-old woman was treated for carbosulfan poisoning with atropine, isotonic saline, and intra-
241 venous mannitol (20%) (60A). Her fight forearm became edematous, cyanotic, and tender at the site of the mannitol infusion and compartment pressures were raised. A fasciotomy was required and recovery occurred over several days.
REFERENCES
1. Zaidi FH, Kinnear PE. Acetazolamide, alternate carbonic anhydrase inhibitors and hypoglycaemic agents: comparing enzymatic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. Br J Ophthalmol 2004; 88: 714-15. 2. Kodjikian L, Durand B, Burillon C, Rouberol E Grange J-D, Renandier P. Acetazolamide-induced thrombocytopenia. Arch Ophthalmol 2004; 122: 1543-4. 3. Goldberg S, Gallily R, Bishara S, Blumenthal EZ. Dorzolamide-induced choroidal detachment in a surgically untreated eye. Am J Ophthalmol 2004; 138: 285~5. 4. Erkens JA, Klungel OH, Stolk RP, Spoelstra JA, Grobbee DE, Leufkens HG. Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients. Pharmacoepidemiol Drug Saf 2004; 13: 139-46. 5. Rais-Bahrami K, Majd M, Veszelovszky E, Short BL. Use of furosemide and hearing loss in neonatal intensive care survivors. Am J Perinatol 2004; 21: 329-32. 6. Zenuk C, Healey J, Dormelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy. Can J Clin Pharmacol 2003; 10: 184-8. 7. Nederfors T, Nauntofte B, Twetman S. Effects of furosernide and bendroflumethiazide on saliva flow rate and composition. Arch Oral Bio12004; 49: 507-13. 8. Alpert SA, Noe HN. Furosemide nephrolithiasis causing ureteral obstruction and urinoma in a preterm neonate. Urology 2004; 64: 589. 9. Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Nacedo E, Gibney N, Tolwani A, Ronco C, Kellum JA. Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32: 1669-77. 10. Dominguez-Ortega J, Martinez-Alonso JC, Dominguez-Ortega C, Fuentes MJ, Frades A, Fernandez-Colino T. Anaphylaxis to oral furosemide. Allergol Immunopathol (Madr) 2003; 31: 345-7. 11. Lee AG, Anderson R, Kardon RH, Wall M. Presumed sulfa allergy in patients with intracranial hypertension treated with acetazolamide or furosemide: cross-reactivity, myth or reality? Am J Ophthalmol 2004; 138:114-18. 12. Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessey S, Bilker WB. Absence
of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. New Engl J Med 2003; 349: 1628-35. 13. Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52: 794-8. 14. Levy DG, Rocha R, Funder JW. Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 2004; 89: 2736-40. 15. Witham MD, Gillespie ND, Struthers AD. Tolerability of spironolactone in patients with chronic heart failure - a cautionary message. Br J Clin Pharmacol 2004; 58: 554-7. 16. Ghislain PD, Bodarwe AD, Vanderdonckt O, Tennstedt D, Marot L, Lachapelle JM. Druginduced eosinophilia and multisystem failure with positive patch-test reaction to spironolactone: DRESS syndrome. Acta Dermatol Venereol 2004; 84: 65-8. 17. Paczynski R-E Osmotherapy. Basic concepts and controversies. Crit Care Clin 1997; 13: 105-29. 18. Better O-S, Rubinstein, I, Winaver J-M, Knocbel J-E Mannitol therapy revisited (19401997). Kidney Int 1997; 52: 886-94. 19. Hansen P-H, Rosenorn J, Westergaard L. Mannitolbehandling ved forhojet intrakranielt tryk. Ugeskr Laeger 1983; 145:1125-7. 20. Node Y, Nakazawa S. Clinical study of mannitol and glycerol on raised intracranial pressure and on their rebound phenomenon. Adv Neurol 1990; 52: 359--63. 21. Sanchez R, Brindis LC, Fierro H, Strecker C, Munoz O. Uso de manitol y dexametasona en el manejo del edema cerebral agudo de origen infeccioso. Bol Med Hosp Infant Mex 1977; 34: 283-90. 22. Spring A. Veranderungen des Laktat-PyruvatSpiegels im Blut auf eine Osmotherapie mit Mannit und Sorbit. Neurochirurgia (Stuttg) 1980; 23: 17681. 23. Roberts I, Schierhout G, Wakai A. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 2003; 2: CD001049. 24. Vialet R, Albanese J, Thomachot L, Antonini F, Bourgouin A, Alliez B, Martin C. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 ml/kg 7.5% saline is more effective than 2 ml/kg 20% mannitol. Crit Care Med 2003; 31: 1683-7.
242 25. Bereczki D, Milialka L, Szatmari S, Fekete K, Di Cesar D, Fulesdi B, Csiba L, Fekete I. Mannitol use in acute stroke: case fatality at 30 days and 1 year. Stroke 2003; 34: 1730-5. 26. Polderman KH, van de Kraats G, Dixon JM, Vandertop WP, Girbes AR. Increases in spinal fluid osmolarity induced by mannitol. Crit Care Med 2003; 31: 584-90. 27. Heimberger K, Samec P, Binder H, Podreka I, Reisner T, Deecke L, Horaczek A, Dittrich C, Steger G, Zimpfer M, et al. Blood brain barrier modification and chemotherapy. Interventional neuroradiology in the treatment of malignant gliomas. Acta Radiol Suppl 1986; 369: 223-6. 28. Yamada K, Takahama H, Nakai O, Takanashi T, Hosoya T. Intra-arterial chemotherapy of malignant glioma after osmotic blood-brain barrier disruption [in Japanese]. Gan To Kagaku Ryoho 1989; 16: 2692-6. 29. Miyagami M, Tsubokawa T, Tazoe M, Kagawa Y. Intra-arterial ACNU chemotherapy employing 20% mannitol osmotic blood-brain barrier disruption for malignant brain tumors. Nenro| Med Chir (Tokyo) 1990; 30: 582-90. 30. Gumerlock MK, Belslie BD, Madsen R, Watts C. Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. J Neurooncol 1992; 12: 33-46. 31. Doolittle ND, Petrillo A, Bell S, Cummings P, Eriksen S. Blood-brain barrier disruption for the treatment of malignant brain tumors: The National Program. J Neurosci Nurs 1998; 30: 81-90. 32. Kobrinsky NL, Packer RJ, Boyett JM, Stanley P, Shiminski-Maher T, Allen JC, Garvin JH, Stewart DI, Finlay JL. Etoposide with or without mannitol for the treatment of recurrent or primarily unresponsive brain tumors: a Children's Cancer Group Study. J Neurooncol. 1999; 45: 47-54. 33. Lou-Moller P, Olsen L, Schierbeck J, Hansen H, Christau B, Bonnevie O. Bisakodyl (Toilax) og peroral mannitol som udrensningsmidler for rontgenundersogelse af colon. Ugeskr Laeger 1983; 145: 3093-6. 34. Noya G, Dettori G, Muscas AG, Delogu L, Antona C, Marongiu G, Frassetto A, Biglioli P. I1 mannitolo nella preparazione del colon alia endoscopia diagnostica ed operativa. Minerva Dietol Gastroenterol 1984; 30: 397-9. 35. Kujat R, Pichlmayr R. Nebenwirkungen verschiedener Spullosungen bei der orthograden Darmspulung. Chirurg Z Geb Operat Med 1983; 54: 669-72. 36. Hares MM, Nevah E, Minervini S, Bentley S, Keighley M, Alexander-Williams J. An attempt to reduce the side effects of mannitol bowel preparation by intravenous infusion. Dis Colon Rectum 1982; 25: 289-91. 37. Beck DE, Fazio VW, Jagelman DG. Comparison of oral lavage methods for preoperative colonic cleansing. Dis Colon Rectum 1986; 29: 699-703. 38. Foord KD, Morcos SK, Ward P. A comparison of mannitol and magnesium citrate preparations for double-contrast barium enema. Clin Radiol 1983; 34: 309-12.
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39. Dimberg M, Norlen H, Allgen LG, Allgen T, Wallin M. A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions. Scand J Urol Nephrol 1992; 26: 241-7. 40. Logic JR, Keenan RA, Whiting PH, Steyn JH. Fluid absorption during transurethral prostatectomy. Br J Urol 1980; 52: 526-8. 41. Hahn RG, Sandfeldt L, Nyman CR. Doubleblind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral resection of the prostate. J Urol 1998; 160: 397-401. 42. Habr-Gama A, Bringel RW, Nahas SC, Araujo SE, Souza-Junior AH, Calache JE, Alves PA. Bowel preparation for colonoscopy: comparison of mannitol and sodium phosphate. Results of a prospective randomized study. Rev Hosp Clin Fac Med Sat Paulo 1999; 54: 187-92. 43. Todorov AT, Mantchev ID, Atanasov TB. Traditional bowel preparation versus osmotic agent marmitol for preoperative colonic cleansing in elective colorectal surgery. Folia Med (Plovdiv) 2002; 44: 36-9. 44. Weidema WF, Van den Boogaard AE, Wesdorp RI, Van Boven CR Greep JM. 24-hour systemic antimicrobial prophylaxis with gentamicin and metronidazole, or metronidazole alone, in elective colorectal surgery after mechanical bowel preparation with mannitol and whole gut irrigation. Acta Chir Belg 1985; 85: 349-53. 45. Bigard M-A, Gauclier P, Lassalle C. Fatal colonic explosion during colonoscopic polypectomy. Gastroenterology 1979; 77: 1307-10. 46. Schunk K, Wiessner J, Schadmand S, Kaltenborn H, Duber C, Brunier A. Zur Frage der Darmkontrastierung in der abdominellen Computertomographie. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1992; 156: 443-7. 47. Schunk K, Kersjes W, Schadmand-Fischer S, Grebe P, Kauczor HU, Thelen M. Eine Mannitollosung als orales Kontrastmittel in der pelvinen MRT. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995; 163: 60-6. 48. Hessels J, Eidhof HH, Steggink J, Roeloffzen WW, Wu K, Tan G, Van de Stadt J, Van Bergeijk L. Assessment of hypolactasia and site-specific intestinal permeability by differential sugar absorption of raffinose, lactose, sucrose and mannitol. Clin Chem Lab Med 2003; 41: 1056--63. 49. Di Leo V, D'Inca R, Diaz-Granado N, Fries W, Venturi C, D'Odorico A, Martines D, Sturniolo GC. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. Am J Gastroentero12003; 98: 2245-52. 50. Carcoana OV, Mathew JE Davis E, Byrne DW, Hayslett JP, Hines RL, Garwood S. Mannitol and dopamine in patients undergoing cardiopulmonary bypass: a randomized clinical trial. Anesth Analg 2003; 97: 1222-9. 51. Santoso JT, Lucci 3rd JA, Coleman RL, Schafer I, Hannigan EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a ran-
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Chapter 21
domized trial.Cancer Chemother Pharmacol 2003; 52: 13-18. 52. Erard AC, Walder B, Ravussin P. Eff~ts de charges equiosmolaires de mannitol 20%, de NaC1 7.5% et de NaC1 0.9% sur l'osmolarit6, l'h6modynamique et les electrolytes plasmatiques. Ann Fr Anesth R6anim 2003; 22: 18-24. 53. Nilsson A, Randmaa I, Hahn RG. Haemodynamic effects of irrigating fluids studied by Doppler ultrasonography in volunteers. Br J Urol 1996; 77: 541~5. 54. Barben J, Roberts M, Chew N, Carlin JB, Robertson CE Repeatability of bronchial responsiveness to mannitol dry powder in children with asthma. Pediatr Pulmonol 2003; 36: 490--4. 55. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003; 22: 491~6. 56. Holzer K, Anderson SD, Chan HK, Douglass J. Mannitol as a challenge test to identify exerciseinduced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003; 167: 534-7.
243 57. Brannan JD, Koskela H, Anderson SD, Chan HK. Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects. Respirology 2002; 7: 37-44. 58. Miyake Y, Miyake K, Maekubo K, Kayazawa E Increase in aqueous flare by a therapeutic dose of mannitol in humans [in Japanese]. Nippon Ganka Gakkai Zasshi 1989; 93:1149-53. 59. Perez-Perez AJ, Pazos B, Sobrado J, Gonzalez L, Gandara A. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22: 573-5. 60. Eroghu A, Uzunlar H. Forearm compartment syndrome after intravenous mannitol extravasation in a carbosulfan poisoning patient. J Toxicol Clin Toxicol 2004; 42: 649~52. 61. Edwards JJ, Samuels D, Fu ES. Forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia. Anesth Analg 2003; 96: 245~5.
Diuretics
21 CARBONIC ANHYDRASE
(SED-14, 669; SEDA-25, 249; SEDA-26, 238; SEDA-27, 22) INHIBITORS
Acetazolamide Fluid balance
Acetazolamide can cause rapid
volume changes. 9 A47-year-old woman with diabetes who took acetazolamide (250 mg bd for 6-days) for left cystoid macular edema developed profound hyperosmolar non-ketotic hyperglycemia (1A). This occurred as the result of marked diuresis and an associated fall in glomerular filtration rate.
Hematologic
Acetazolamide can cause rapid hematological changes, including thrombocy-
topenia. 9 A67-year-old man developed isolated thrombo-
cytopenia (platelet count 31 • 109/1) after taking acetazolamide 250/mg day for 2 days for raised intraocular pressure (2A). Several months later acetazolamide 375 mg/day was prescribed again and 2 weeks later he developed extensive purpura and a platelet count of 3 • 109/1. Acetazolamide was withdrawn and the platelet count rose spontaneously to 20, 73, and 246 • 109/1 after 1, 3, and 10 days respectively.
Dorzolamide Sensory systems Eyes that have not undergone surgery have not been reported to undergo choroidal detachment with topical hypotensive agents. 9 A76-year-old woman with a 7-year history of open-angle glaucoma presented with distorted visual acuity after applying two doses of dorzolamide eye-drops 2% bd to both eyes (3A). Other 92005 Published by Elsevier B.V.
SideEffectsof Drugs, Annual 28
J.K. Aronson, ed.
systemic medications included hydrochlorothiazide and verapamil. There was a peripheral choroidal detachment in the left eye, which completely resolved 1 week after withdrawal of dorzolamide together with topical glucocorticoid therapy. In this case, the systemic hydrochlorothiazide may have sensitized the choroidal epithelium sufficiently to result in aqueous fluid shutdown.
THIAZIDE AND LOOP
(SED-14, 656; SEDA-25, 252; SEDA-26, 239; SEDA-27, 220)
DIURETICS
Thiazides Musculoskeletal
In a nested case-control study in patients with type 2 diabetes there were 26 cases of a first leg amputation among 12 140 cases. Subjects who used thiazide diuretics alone or together with other antihypertensive medications had a higher risk of leg amputation (crude odds ratio = 6.11) compared with subjects taking ACE inhibitor monotherapy. Thiazide diuretics were also associated with an increased risk of leg amputation than non-thiazide antihypertensive drugs (adjusted odds ratio = 7.04). These findings suggest that thiazide-type diuretics be used cautiously in patients with type 2 diabetes particularly when there is significant lower limb peripheral vascular disease (4c).
Furosemide Hearing loss is a significant problem in survivors in neonatal intensive care units and has been attributed to underlying disease processes and/or exposure to ototoxic drugs, including furosemide. A retrospective chart review (July 2000 to January Sensory systems
233
234 2002) of all survivors in a neonatal intensive care unit was undertaken to evaluate the effect of furosemide on hearing loss (5M). Of the 57 neonates who had received furosemide nine had a subsequent abnormal heating screen, and of the 207 neonates who had not received furosemide 33 also had an abnormal hearing screen. This suggests that hearing loss in these neonates is not directly related to the use of furosemide.
Nutrition
Furosemide has been associated with thiamine deficiency in patients with heart failure. Erythrocyte transketolase activity suggested severe thiamine deficiency in 24 of 25 patients with heart failure who were taking at least 80 mg/day of furosemide and in four of seven patients who were taking 40 rag/day (OR = 19; CI = 1.1,601) (6c). Thiamine status was not associated with any other clinical variables. These findings suggest that thiamine deficiency occurs in a substantial proportion of patients with heart failure who are taking furosemide; however, this is of unclear cfinical significance.
Salivary glands Diuretics cause altered salivary flow rate and composition and have been associated with both subjective and objective evidence of xerostomia. In a randomized trial in 12 healthy women randomly assignment to placebo, bendroflumethiazide (2.5 rag/day for 7 days) and furosemide (40 mg/day for 7 days), xerostomia increased with furosemide in conjunction with a reduction in submandibularsublingual salivary secretion (7c). This was particularly so at lunchtime. This suggests that diuretics may potentiate dryness of the mouth and should be used carefully in patients with abnormal salivary flow.
Urinary tract A 900-gram girl born before term with bronchopulmonary dysplasia developed ureteral obstruction, urinoma, and acute renal insufficiency as a result of furosemiderelated hypercalciuria (cumulative dose 27.5 mg) and nephrolithiasis (8A). Percutaneous drainage of the urinoma plus conversion to hydrochlorothiazide resolved the urinoma and hydronephrosis. Acute renal insufficiency carries a high mortality and morbidity. Diuretics may increase mortality in patients with acute renal insufficiency (SEDA-27, 221), but this has not been
Chapter 21
Domenic A. Sica
studied prospectively. In a prospective, multicenter, multinational, epidemiological study of 1743 consecutive patients, who were either treated with renal replacement therapy or who fulfilled predefined criteria for acute renal insufficiency, about 70% were taking diuretics at enrolment (9M). Severe sepsis/septic shock (48%), major surgery (39%), low cardiac output (30%), and hypovolemia (28%) were the most common conditions associated with the development of acute renal insufficiency. Furosemide was the most common diuretic used (98%). In all three multivariate models, diuretic use was not associated with a significantly increased risk of mortality. The use of diuretics in patients with acute renal insufficiency should continue, but only according to a specific need to control volume excess.
Immunologic
Furosemide rarely causes type 1 allergic reactions. A 24-year-old woman took one tablet of furosernide 40 mg and 10 minutes later developed oral itching, generalized urticaria, facial angioedema, dyspnea, and hypotension (10A). She recovered after the administration of parenteral adrenaline, methylprednisolone, and diphenhydramine. A furosemide skin prick test 10 mg/ml was negative. An intraderreal skin test was positive for furosemide 1% and sulfamethoxazole 0.03 mg/ml.
IgE-mediated reactions to furosemide are infrequent, but can be life-threatening. The positive intradermal test to sulfamethoxazole in this case raises the question of cross-reactivity between non-aromatic and antimicrobial sulfonamides. There is little clinical or pharmacological evidence that a self-reported sulfa allergy is likely to be associated with a life-threatening crossreaction with acetazolamide or furosemide (11 M, 12M). Most patients who report sulfa allergy have actually had an adverse reaction to a sulfonamide antimicrobial drug. There are significant structural differences between sulfonamide antibiotics and other sulfonamide non-antimicrobial drugs such as furosemide and acetazolamide, and generally cross-reactivity would not be expected. In a retrospective cohort study using the General Practice Research Base in the UK, 969 cases with a so-called allergic reaction to an antimicrobial sulfonamide were reviewed (12M).
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Chapter21
Only 96 (9.9%) had an allergic reaction after receiving a non-antimicrobial sulfonamide. Of 19 257 who had no allergic reaction after a antimicrobial sulfonamide, 315 (1.6%) had an allergic reaction However, the risk of allergic reactions was even greater after the use of a penicillin among patients with a prior hypersensitivity reaction to a antimicrobial sulfonamide, compared with patients with no such history (adjusted odds ratio = 3.9) after receiving a non-antimicrobial sulfonamide (adjusted odds ratio = 2.8). In addition, among those with a prior hypersensitivity reaction after an antimicrobial sulfonamide, the risk of an allergic reaction after the subsequent receipt of a nonantimicrobial sulfonamide was lower than the risk of an allergic reaction with penicillin (adjusted odds ratio = 0.7). Finally, the risk of an allergic reaction after an antimicrobial sulfonamide was lower among patients with a history of hypersensitivity to an antimicrobial sulfonamide than among patients with a history of hypersensitivity to penicillins (adjusted odds ratio = 0.6). These results suggest that there is an association between hypersensitivity after an antimicrobial sulfonamide and a subsequent allergic reaction after a non-antimicrobial sulfonamide, but this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.
Drug interactions
Of 10 615 elderly patients continuously taking lithium for over 10 years, 413 (3.9%) were admitted to the hospital at least once with lithium toxicity. After adjustment for potential confounders, there was a 5.5-fold increase in the relative risk of lithium toxicity within 1 month of starting therapy with a loop diuretic (13c). Thiazide diuretics were not independently associated with an increased risk of hospitalization for lithium toxicity. This population-based nested case-control study stresses the importance of monitoring for lithium toxicity whenever a loop diuretic is started.
235
ALDOSTERONE
RECEPTOR
(SED-14,674; SEDA-25, 254; SEDA-240; SEDA-27, 221) ANTAGONISTS
Eplerenone Electrolyte balance HyperkaIemia is always a consideration with spironolactone and eplerenone, but the relation between a beneficial response to eplerenone and the change in serum potassium concentration has been poorly characterized. In 397 hypertensive patients (responders and non-responders) taking eplerenone 50200 mg/day without other susceptibility factors for hyperkalemia, eplerenone caused an increase in serum potassium concentration of 0.2 mmol/1 (14c). The blood pressure lowering effect of eplerenone did not correlate with the change in serum potassium concentration. This suggests that in patients with uncomplicated hypertension, eplerenone can be used without a significant risk of hyperkalemia.
Spironolactone U r i n a r y t r a c t Of 226 patients with heart failure in a retrospective analysis, 25 stopped therapy because of renal dysfunction, 13 primarily because of hyperkalemia and 12 primarily because of a rising creatinine (15c). The mean baseline creatinine in the latter was 140 ~tmol/1, rising to a mean of 197 kLmol/1 at the time of stopping therapy. Eight of 11 patients had a serum creatinine over 200 ~tmol/1. Spironolactone should be considered as one of the several pharmacological factors that can cause deterioration of renal function in heart failure. Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been attributed to spironolactone. 9 A58-year-old man developed erythroderma, fever, anorexia, peripheral edema, eosinophilia, and multi-organ failure while taking several drugs, including spironolactone (16A). All the medications were stopped and the condition completely remitted over 4 months. Patch testing was positive for spironolactone.
236
OSMOTIC DIURETICS (SED-14, 1162, 1236)
Mannitol
Uses of mannitol The number o f uses o f mannitol continues to increase.
Reducing raised intracranial pressure
The use o f mannitol in the treatment o f raised intracraniat pressure has been reviewed, in the light o f disagreements about the appropriate timing o f administration, the optimal fluid management protocol, and the mechanisms of action o f osmotic diuretics (17R-19R ). The effects o f four methods o f infusion o f mannitol and glycerol on raised intracranial pressure, as monitored by epidural pressure recordings, have been studied in 65 patients (20c). A. mannitol 0.5 g/kg was infused over 15, 30, or 60 minutes; B. mannitol 1.0 g/kg was infused over 30, 60, or 90 minutes; C. glycerol 0.5 g/kg in 5%fructose was infused over 30, 60, or 90 minutes; D. glycerol 1.0 g/kg was infused over 60, 120, or 180 minutes. In group A, there were no differences in the reduction in intracranial pressure across the three infusion rates. In group B, the degree o f reduction in intracranial pressure increased with shorter times o f infusion. In groups C and D the reduction in intracraniaI pressure was inversely related to the rate o f infusion. In each group, the slower the infusion rate o f the same dosage, the longer the reduction in intracranial pressure lasted. There was a rebound increase in intracranial pressure in 12% o f those given mannitol and 34% o f those given glycerol The dose and the rate o f mannitol infusion did not affect the rebound. In 22 patients with meningoencephalitis and hypertensive cranial syndrome from cerebral edema, mannitol was given to 13 and dexamethasone to nine (21c). There were three therapeutic failures in those given mannitol and none in those given dexamethasone, although the two
Chapter 21
Domenic A. Sica
drugs had similar effects on the duration o f the hypertensive cranial syndrome (39--44 hours). The patients who were treated with mannitol had hyponatremia after 48 hours. In 43 patients, osmotherapy with mannitol 20% and sorbito140% increased the serum concentration o f lactate but not pyruvate, causing an increased ratio o f lactate to pyruvate (22c). Sorbitol had the greater effect, with a maximum at 1 hour. Mannitol had its maximum effect at 4 hours. The author concluded that acidosis, shock, diabetes mellitus, and hepatic dysfunctions increase the risk o f osmotherapy, especially with sorbitol. Randomized trials o f mannitol in patients with acute traumatic brain injury of any severity have been reviewed (23M). In the preoperative management o f patients with acute intracranial hemorrhage high-dose mannitol reduced mortality (RR = 0.55; 95% CI = 0.36, 0.84) and reduced death and severe disability (RR = 0.58; 95% CI = 0.45, 0.74) compared with conventional-dose mannitol. In one trial treatment intended to lower intracranial pressure was compared with "standard care" (RR f o r death = 0.83; 95% CI = 0.47, 1.46). In one trial mannitol and pentobarbital were compared (RR f o r death = 0.85; 95% CI = 0.52, 1.38). In one trial pre-hospital mannitol was compared with placebo (RR for death = 1.75; 95% CI = 0.48, 6.38). The reviewers concluded that high-dose mannitol is preferable to conventional-dose mannitol in the pre-operative management o f patients with acute intracranial hematomas. However, there is little evidence about the use o f mannitol as a continuous infusion in patients with raised intracranial pressure who do not have an operable intracraniaI hematoma. In 20 patients with head trauma and persistent coma who required infusions o f an osmotic agent to treat episodes o f intracranial hypertension resistant to standard modes o f therapy, isovolumic infusions o f either 7.5% hypertonic saline reduced the number o f episodes o f intracranial hypertension per day (6.9 versus 13.3) and the daily duration o f episodes of intracranial hypertension (67 versus 131 minutes) compared with 20% mannitol (24c). Stroke In 805 patients who were given intravenous mannitol (mean dose, 47 g/day; mean duration, 6 days) or no treatment within 72
Diuretics
Chapter 21
hours of the onset of a stroke, the case fatality was 25% versus 16% at 30 days and 38% versus 25% at 1 year (25c). The prognostic scores on the Scandinavian Neurological Stroke Scale were similar in treated and untreated patients, both in ischemic and hemorrhagic strokes. However, the patient groups differed in several factors that might have affected survival. Thus, this uncontrolled study was inconclusive. Serum and cerebrospinal fluid osmolarity were measured in 30 patients with severe head injuries or subarachnoid hemorrhage, 10 of whom received mannitol for at least 72 hours, 10 of whom received it for 24-48 hours, and 10 of whom were controls (26c). Serum osmolarity increased quickly in all those who received mannitol and was unchanged in controls. Average cerebrospinal fluid osmolarity increased slowly in all those who received mannitol and was unchanged in controls. This is a potentially dangerous effect and the authors recommended that cerebrospinal fluid osmoIarity should be measured regularly in all patients who receive mannitol for longer than 24 hours. Disrupting the blood-brain barrier Mannitol has been used to disrupt the blood-brain barrier temporarily in order to allow better penetration of chemotherapeutic drugs. In eight patients with gliomas and one with a primary lymphoma of the central nervous system the blood-brain or blood-tumor barrier was reversibly opened by intra-arterial injection of hyperosmolar mannitol 25% (27c). There was tumor regression or a tumor progression-free interval in five patients. In 10 patients with malignant gliomas intraarterial chemotherapy with 5-fluorouracil, nitrosourea, or interferon beta was given after osmotic blood-brain barrier disruption with intraarterial 20% mannitol (28c). In nine evaluable cases there were one complete and three partial responses; in five there was no change and no progressive disease on CT. The most untoward effect was myelosuppression: platelet and leukocyte counts fell below 20 • 109/I and 2 • 109/1 respectively in threepatients, of whom two died of severe infections. The other complications were eye pain during mannitol infusion in all cases in which selective catheterization of the internal carotid artery failed to pass the origin of the ophthalmic artery. There was reduced activity in 70%, nausea and vomiting
237
in 50%, swelling of the external decompression area in 33%, and increased neurological deficits in 20%. However, all these adverse effects were transient. Of 21 patients with malignant brain tumors, 16 were treated by operation, irradiation, and two or more courses of intracarotid infusion of nitrosourea 100 mg after 20% mannito1200 ml, and five were treated similarly but without mannitol (29c). The 2-year survival rate in those who received mannitol was 79% (11 of 14 cases followed for longer than 2 years) and the 3-year survival rate was 67%. Five of seven patients with grade 4 astrocytomas survived for more than 18 months, whereas four of five patients with grade 4 astrocytomas who did not receive mannitol died within 18 months. Over 4 years, 37 patients with high-grade malignant gliomas underwent 246 treatment procedures with a combination of methotrexate, cyclophosphamide, and procarbazine given together with hyperosmolar mannitol-induced transient breakdown of the blood-brain barrier (30~). There were complete remissions in 16% and 24 patients (65%) had partial or temporary remissions. Progression-free intervals were 147 (mean 15) months and median survival was 22 months. Neurotoxicity was minimal with one periprocedural death and five instances of worsened neurological deficits after a procedure. The delivery of chemotherapeutic agents in the treatment of malignant brain tumors is improved by osmotic opening of the bloodbrain barrier by prior infusion of mannitol into the internal carotid or vertebral artery. Over 4200 blood-brain barrier disruption procedures have been performed in over 400 patients with primary central nervous system lymphomas, gliomas, primitive neuroectoderreal tumors, germ cell and metastatic cancers in the National Blood-Brain Barrier Program (31c). In patients with primary nervous system lymphomas, long-lasting responses have been obtained without loss of cognitive function and without the use of radiotherapy. The results in patients with primitive neuroectodermal tumors and germ cell tumors are also said to be very encouraging. The efficacy of mannitol in augmenting the tumoricidal effect of etoposide has been studied in 99 children aged 1-21 years with recurrent brain tumors (32c). They were randomly
238 assigned to intravenous etoposide 150 mg/m 2 with or without mannitol 15 g/m 2, daily for 5 days every 3 weeks for 1 year or until disease progression or death. CT or MRI scans, obtained after three cycles of therapy, were compared with pre-therapy scans. 0 f 8 7 evaluable patients, 12 had an objective response according to the radiologist and of 66 patients reviewed centrally, seven responded (two of 12 low grade astrocytomas, four of 26 medulloblastomas or primitive neuroectodermal tumors, one of 13 high-grade astrocytomas, and one of 15 brain stem gliomas). Survival at 1 year was 53% for low grade astrocytomas, 38% for medulloblastomas or primitive neuroectodermal tumors, 28% for high-grade astrocytomas and 9% for brain stem gliomas. Mannitol had no beneficial effect. Use in bowel cleansing Mannitol has been used for preoperative bowel cleansing before radiological investigations (33c), diagnostic and operative endoscopy (34c), and bowel surgery. In whole gut irrigation mannitol is badly tolerated and leaves a bowel full of gas and fluid although it causes only small changes in serum electrolytes (35R). In a study of the effect of an intravenous infusion of saline on the volume of rectal effluent and quality of bowel preparation produced by a smaller oral dose of mannitol, 19patients drank 2-3 1 of 5% mannitol, supplemented by an intravenous infusion of isotonic saline and 19 patients drank 4-5 1 of 5% mannitol (36c). The volume of rectal effluent and the quality of bowel preparation was the same in both groups. Loss of sodium in the oral group was corrected by the intravenous infusion, but the infusion resulted in greater water retention. There was no difference in the incidence of vomiting between the two groups. Polyethylene glycol electrolyte lavage solution has been compared with 10% mannitol for preoperative colonic cleansing in 80 patients (37c). Colonic cleansing was better with polyethylene glycol (90% optimal cleansing versus 75%). Mannitol caused subclinical dehydration according to hematological, biochemical, and weight changes before and after bowel preparation and caused more nausea, cramps, and abdominal pain. Two patients given mannitol had combustible amounts of hydrogen gas in the colon.
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Three formulations, two based on magnesium citrate and one an optimized oral mannitol regimen, have been compared for their effectiveness in clearing the large bowel before double-contrast barium enema and for effects on barium mucosal coating (38c). The formulations based on magnesium citrate were equally good and caused significantly less nausea and vomiting than mannitol. The authors concluded that mannitol should not be used for preparing the bowel for barium enema. Two hypotonic non-hemolysing irrigating solutions, sorbitol + mannitol (2% + 1%) and glycine (1.5%), have been compared in patients undergoing transurethral resection of the prostate (39c). Ethanol (1%) was added to the irrigating f u i d as a marker to allow early detection of fluid absorption by breath analysis. There was very little absorption (less than 1 1). However, in other cases large volumes of fluid have been absorbed. In 39 patients having transurethral resection of the prostate for benign prostatic hyperplasia, large quantities of mannitol, which was used as the irrigating fuid, entered the circulation (40c). There was a corresponding fall in serum sodium concentration. Patients who had serum mannitol concentrations over 4 mg/ml had hypotension and bradycardia; because they were nearly all hypovolemic, the bradycardia was thought to be inappropriate. Irrigating fluid bags containing mannitol 3% or glycine 1.5%, both with added ethanol 1% as an indicator of fluid absorption, were used to investigate adverse effects in a randomized, double-blind study during 394 transurethraI prostatic resections (41c). The incidence of 13 symptoms was studied in 52 patients (13%) who absorbed more than 500 ml of fluid. The incidence of circulatory symptoms did not differ between the fluids, but the risk of neurological symptoms, such as nausea, was 4.8 times higher with glycine 1.5%. An increase of 1000 ml in the volume of irrigant absorbed increased the overall risk of circulatory symptoms by a factor of 3.4 and the risk of neurological symptoms by a factor of 4.4. The authors concluded that absorption of mannitol 3% during transurethral prostatic resection is associated with fewer neurological symptoms than glycine 1.5%. In 80 patients randomized for precolonoscopic cleansing with either 10% mannitol 750
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ml or sodium phosphate 180 ml there were statistically significant differences in serum sodium, phosphorus, potassium, and calcium between the two groups, but no clinical symptoms and no significant differences in the frequencies o f adverse effects (42c). Six o f eight patients who were treated with sodium phosphate and who had mannitol f o r a previous colonoscopy preferred sodium phosphate. The endoscopists, who were blinded to the treatment, reported excellent or good bowel preparation in 85% o f those prepared with sodium phosphate versus 83% f o r mannitol. The authors concluded that although the quality o f preparation and the frequencies o f adverse effects were similar with the two solutions, retention o f sodium and phosphate ions contraindicates the use o f sodium phosphate in patients with renal insufficiency, cirrhosis, ascites, and heart failure. In a retrospective study o f patients who underwent elective surgery f o r colorectal carcinomas, traditional bowel preparation was performed the day before the operation either with oral castor oil 30 ml and three soap enemas (n = 154) or with mannitol 500 ml (n = 36) (43c). There were infectious wound complications in 26 patients (17%) pretreated with castor oil compared with 13 patients (36%) treated with mannitol. There were no differences in the incidence o f anastomotic leaks or mortality rate. Systemic antimicrobial prophylaxis with metronidazole and gentamicin has been compared with metronidazole alone in elective colorectal surgery in a prospective randomized trial in which all the patients received 10% mannitol solution before surgery (44c). Although there were no serious infections in either group, the incidence o f superficial wound infections was relatively high: 19% in those given metronidazole and gentamicin prophylaxis and 25% in those given metronidazole alone. Escherichia coIi was isolated from all these wounds, and no obligate anerobic bacteria were cultured. The high rate o f wound infection was probably caused by overgrowth after irrigation, due to residues o f mannitoI in the colon, which serve as a nutrient f o r Escherichia coli. Both sets o f authors concluded that mannitol should not be used f o r preoperative mechanical preparation o f the large bowel before elective colorectaI surgery.
239 Hydrogen gas can accumulate in the colon after the administration o f mannitol (37c). This can cause a risk o f explosion. 9 Colonic explosion during colonoscopic polypectomy occurred after mannitol had been used for bowel preparation and the colon was completely clean (45A). In spite of emergency surgery, with transfusion of 45 units of blood, uncontrollable hemorrhage persisted from multiple bleeding points and the patient died.
Use as a radiocontrast medium
In 56patients undergoing abdominal CT the gastrointestinal tract was defined by negative contrast with 2.5% mannitol instead o f the conventional positive contrast from an iodine-containing contrast medium (46c). The number o f artifacts due to high-contrast boundaries was slightly greater with negative contrast than it would have been with positive contrast, but differentiation o f the gastrointestinal tract from other abdominal organs was equally good. Negative contrast was poor f o r diagnosing cystic tumors but much better than positive contrast f o r evaluating the wall o f the gastrointestinal tract. The effect o f oral mannitol in an aqueous solution in enhancing pelvic MRI has been reported in a retrospective study in 72 patients with suspected or proven pelvic abnormalities: In 36 patients bowel marking was not carried out and in 36 patients the bowel was contrast-enhanced by oral mannitol 1000 ml (47r Mannitol significantly improved delineation o f the intestinal structures and pelvic organs or pathological lesions, but eight patients had diarrhea, nausea, or meteorism.
Diagnosis of diarrhea In chronic diarrhea intestinal permeability to sugars, such as raffinose, lactose, lactulose, sucrose and mannitol (48c), can detect intestinal damage. The absorption o f a combined dose o f lactulose and mannitol has been studied in 261 consecutive patients with three or more bowel movements daily f o r at least 3 weeks; 120 (46%) were found to have an organic cause f o r chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed (49c). The lactulose/mannitol test and C-reactive protein were independent predictors f o r the final diagnosis o f an organic cause o f chronic diarrhea, with odds ratios o f l.5 (95% CI = 1.29, 1.78) and 5.2 (95% CI = 1.90, 14.12) respectively.
240 Cardiopulmonary bypass The effects of mannitol and dopamine, alone and in combination, on beta2-microgIobulin excretion rates in 100 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass have been studied in a double-blind, randomized, placebo-controlled study (50c). Mannitol 1 g/kg was added to the cardiopulmonary bypass prime and dopamine 2 micrograms/kg/minute was given from the time of induction of anesthesia to 1 hour after bypass. Dopamine significantly increased the excretion rate of beta2-microglobulin compared with placebo. Thus, rather than being protective during cardiopulmonary bypass, dopamine reduces renal tubular dysfunction. This effect was not ameliorated by the addition of mannitol. Treatment of cisplatin nephrotoxieity Saline alone, saline + furosemide, and saline + mannitol have been used to prevent nephrotoxicity in 49 women who received cisplatin 75 mg/m2 every 3 weeks (51c). Hydration with saline or saline + furosemide was associated with less cisplatin nephrotoxicity than hydration with saline + mannitol. Equiosmolar loads of mannitol 20% and hypertonic saline 7.5% over 10 minutes have been compared with isotonic saline in 30 ASA I and II patients undergoing non-hemorrhagic surgery under general anesthesia (52c). The serum sodium concentration was lowest after mannitol (129 mmol/l) at the end of the infusion and highest after hypertonic saline (151 mmol/1), with normalization at 60 minutes. The hemodynamic effects were similar in the three groups. Temperature was lower after isotonic saline, because of the volume infused. Cardiovascular Glycine (1% or 1.5%) 15 ml/kg, or 3% mannitol (all containing 1% ethanol), or sorbitol 2% + mannitol 1% (with no ethanol) were infused intravenously over 20 minutes into 10 healthy men to determine their hemodynamic effects using Doppler ultrasonography (53c). All reduced cardiac output 30 minutes after infusion, and glycine reduced the heart rate and cardiac output and raised mean arterial pressure, indicating an increase in systemic resistance. Almost identical breathethanol curves were obtained with the three
Chapter 21
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fluids containing ethanol and all of them caused slight hypoglycemia. There was no evidence of ethanol-induced tachycardia. Respiratory Inhaled mannitol increases airway responsiveness in asthmatic subjects (54 c) and may act through mast cell activation (55c). It has been used to investigate the effects of therapeutic drugs or to predict responsiveness to their effects and to determine susceptibility to exercise-induced bronchoconstriction (56c). In 18 asthmatic subjects the inhaled glucocorticoid budesonide caused a reduction in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms (57c).
Sensory systems The effects of intravenous mannitol on aqueous fluid protein concentration have been evaluated in healthy young adults (average age 20 years) and older adults (average age 61 years), and in patients with diabetes mellitus, hypertension, or pseudoexfoliation syndrome who were about to undergo intraocular surgery (average age 66 years) (58c). Mannitol increased aqueous humor protein concentration in all subjects, with a maximum effects at around 1 hour. The magnitude and the duration of the effect were significantly greater in the healthy older subjects than in the young subjects, but the same in older adults with and without diseases. The effect was reversed within 6 hours. Urinary tract Four cases of acute renal insufficiency have been described in a series of men aged 20--42 years who received mannitol 1172 (SD 439) g over 58 (28) hours (59A). The onset of acute renal insufficiency was detected 48 (22) hours after the start of infusion. All the patients had dilutional hyponatremia (average 120 mmol/l), and serum hyperosmolality (osmolar gap 70 mosm/kg water). In the three patients with anuria, in whom hemodialysis was performed, there was immediate recovery of diuresis. This emphasizes the risk of renal insufficiency with mannitol and stresses the importance of early hemodialysis. Mannitol is dialysable, and functional recovery is prompt once its suppressive effect on renal perfusion is eliminated.
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M u s c u l o s k e l e t a l Mannitol can cause a compartment syndrome if it extravasates into soft tissues (60 A, 61A). 9 A17-year-old woman was treated for carbosulfan poisoning with atropine, isotonic saline, and intra-
241 venous mannitol (20%) (60A). Her fight forearm became edematous, cyanotic, and tender at the site of the mannitol infusion and compartment pressures were raised. A fasciotomy was required and recovery occurred over several days.
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39. Dimberg M, Norlen H, Allgen LG, Allgen T, Wallin M. A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions. Scand J Urol Nephrol 1992; 26: 241-7. 40. Logic JR, Keenan RA, Whiting PH, Steyn JH. Fluid absorption during transurethral prostatectomy. Br J Urol 1980; 52: 526-8. 41. Hahn RG, Sandfeldt L, Nyman CR. Doubleblind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral resection of the prostate. J Urol 1998; 160: 397-401. 42. Habr-Gama A, Bringel RW, Nahas SC, Araujo SE, Souza-Junior AH, Calache JE, Alves PA. Bowel preparation for colonoscopy: comparison of mannitol and sodium phosphate. Results of a prospective randomized study. Rev Hosp Clin Fac Med Sat Paulo 1999; 54: 187-92. 43. Todorov AT, Mantchev ID, Atanasov TB. Traditional bowel preparation versus osmotic agent marmitol for preoperative colonic cleansing in elective colorectal surgery. Folia Med (Plovdiv) 2002; 44: 36-9. 44. Weidema WF, Van den Boogaard AE, Wesdorp RI, Van Boven CR Greep JM. 24-hour systemic antimicrobial prophylaxis with gentamicin and metronidazole, or metronidazole alone, in elective colorectal surgery after mechanical bowel preparation with mannitol and whole gut irrigation. Acta Chir Belg 1985; 85: 349-53. 45. Bigard M-A, Gauclier P, Lassalle C. Fatal colonic explosion during colonoscopic polypectomy. Gastroenterology 1979; 77: 1307-10. 46. Schunk K, Wiessner J, Schadmand S, Kaltenborn H, Duber C, Brunier A. Zur Frage der Darmkontrastierung in der abdominellen Computertomographie. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1992; 156: 443-7. 47. Schunk K, Kersjes W, Schadmand-Fischer S, Grebe P, Kauczor HU, Thelen M. Eine Mannitollosung als orales Kontrastmittel in der pelvinen MRT. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995; 163: 60-6. 48. Hessels J, Eidhof HH, Steggink J, Roeloffzen WW, Wu K, Tan G, Van de Stadt J, Van Bergeijk L. Assessment of hypolactasia and site-specific intestinal permeability by differential sugar absorption of raffinose, lactose, sucrose and mannitol. Clin Chem Lab Med 2003; 41: 1056--63. 49. Di Leo V, D'Inca R, Diaz-Granado N, Fries W, Venturi C, D'Odorico A, Martines D, Sturniolo GC. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. Am J Gastroentero12003; 98: 2245-52. 50. Carcoana OV, Mathew JE Davis E, Byrne DW, Hayslett JP, Hines RL, Garwood S. Mannitol and dopamine in patients undergoing cardiopulmonary bypass: a randomized clinical trial. Anesth Analg 2003; 97: 1222-9. 51. Santoso JT, Lucci 3rd JA, Coleman RL, Schafer I, Hannigan EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a ran-
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domized trial.Cancer Chemother Pharmacol 2003; 52: 13-18. 52. Erard AC, Walder B, Ravussin P. Eff~ts de charges equiosmolaires de mannitol 20%, de NaC1 7.5% et de NaC1 0.9% sur l'osmolarit6, l'h6modynamique et les electrolytes plasmatiques. Ann Fr Anesth R6anim 2003; 22: 18-24. 53. Nilsson A, Randmaa I, Hahn RG. Haemodynamic effects of irrigating fluids studied by Doppler ultrasonography in volunteers. Br J Urol 1996; 77: 541~5. 54. Barben J, Roberts M, Chew N, Carlin JB, Robertson CE Repeatability of bronchial responsiveness to mannitol dry powder in children with asthma. Pediatr Pulmonol 2003; 36: 490--4. 55. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003; 22: 491~6. 56. Holzer K, Anderson SD, Chan HK, Douglass J. Mannitol as a challenge test to identify exerciseinduced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003; 167: 534-7.
243 57. Brannan JD, Koskela H, Anderson SD, Chan HK. Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects. Respirology 2002; 7: 37-44. 58. Miyake Y, Miyake K, Maekubo K, Kayazawa E Increase in aqueous flare by a therapeutic dose of mannitol in humans [in Japanese]. Nippon Ganka Gakkai Zasshi 1989; 93:1149-53. 59. Perez-Perez AJ, Pazos B, Sobrado J, Gonzalez L, Gandara A. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22: 573-5. 60. Eroghu A, Uzunlar H. Forearm compartment syndrome after intravenous mannitol extravasation in a carbosulfan poisoning patient. J Toxicol Clin Toxicol 2004; 42: 649~52. 61. Edwards JJ, Samuels D, Fu ES. Forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia. Anesth Analg 2003; 96: 245~5.