British Journal of Anaesthesia 1990; 64: 159-162
ISOFLURANE SEDATION FOR PATIENTS UNDERGOING MECHANICAL VENTILATION: METABOLISM TO INORGANIC FLUORIDE AND RENAL EFFECTS K. L. KONG, J. E. TYLER, S. M. WILLATTS AND C. PRYS-ROBERTS
We have shown that subanaesthetic concentrations of isoflurane (0.1-0.6%) provide a useful alternative technique for sedation of patients undergoing ventilation in the ITU [1]. Many critically ill patients may be expected to be receiving drug treatment which could result in hepatic enzyme induction. The metabolism of isoflurane to inorganic fluoride (F~) and its renal effects in these patients were therefore studied. PATIENTS AND METHODS
We studied 60 patients who required mechanical ventilation in the ITU. Patients were excluded if
Arterial blood samples were collected for measurement of plasma F~ at baseline, at the end of the period of trial sedation, and at 24 h after discontinuing the trial sedative. It was realized K.L.KONG*, M.B.B.S., F.F.A.R.C.S; S. M. WILLATTS, F.F.A.R.C.S., F.R.C.P.; C. PRYS-ROBERTS, M.A., D.M., PH.D., F.F.A.R.C.S., F.F.A.R.A.C.S., Sir Humphry Davy Department of
Anaesthesia, Bristol Royal Infirmary, Bristol BS2 8HW. J. E. TYLER, M.SC, PH.D., F.R.S.C, Medical Research Council
Dental Group, The Dental School, Lower Maudlin Street, Bristol BS1 2LY. Accepted for Publication: July 26, 1989. •Present address for correspondence: University Department of Anaesthesia, Queen Elizabeth Hospital, Birmingham B15 2TH.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
they were pregnant, had head injury or were in coma, were already under an established scheme The metabolism and renal effects of isoflurane of sedation, had a history of allergic response to sedation were studied for 24 h in patients morphine or benzodiazepines, were grossly obese undergoing mechanical ventilation. Forty-six or had uncontrolled haemorrhage. The study was patients admitted to our intensive therapy unit approved by the Bristol and Weston District were allocated randomly to receive either Ethics Committee. Informed consent for par0.1-0.6% isoflurane or midazolam 0.01-0.2 mg ticipation was obtained either from the patient or kg-1 / r ' for sedation. In 26 patients sedated with from the next of kin. Patients were allocated isoflurane, plasma inorganic fluoride increased randomly to receive either 0.1-0.6% isoflurane in i.v. from a mean concentration of 4.03 fimollitre'1 to an air-oxygen mixture or a continuous 1 1 infusion of midazolam 0.01-0.2 mg kg" h" for 13.57 fimol litre-' 12 h after stopping sedation. sedation. In those patients who received isoflurane Plasma inorganic fluoride concentrations in 20 patients sedated with midazolam were un- for sedation, end-tidal concentrations of the agent changed from baseline values (mean 5.32 txmol were measured with a Siemens Gas Monitor and litre-'). Serum electrolyte, urea and creatinine MAC hours of isoflurane calculated. By definition, concentrations, and urine output rates during MAC is not directly applicable to sedated patients and after sedation in patients who received and the end-tidal concentrations and duration of isoflurane were similar to those who received sedation were used to calculate the "volume per midazolam. We conclude that, following iso- cent hours " of isoflurane in each patient. The dose flurane sedation for up to 24 h, metabolism to of sedative was adjusted to maintain a desired inorganic fluoride is insufficient to cause clinical degree of sedation for as long as possible. The trial sedative was stopped either when the patient was renal dysfunction. judged ready for weaning from ventilatory support, or at 24 h (whichever was earlier). If sedation KEY WORDS was required beyond 24 h, an alternative scheme Anaesthetics inhalation: isoflurane. Intensive care: sedation. Metabolism: fluoride. of sedation was substituted. SUMMARY
BRITISH JOURNAL OF ANAESTHESIA
160
RESULTS
Of the 60 patients studied, results from 14 patients were incomplete either because they died during the study or because they had to return to theatre before blood sampling was completed. Results from the remaining 46 patients were analysed. Table I shows the details of these patients, 26 of
Before sedation
End of sedation
24 h after sedation
1 . Mean (SEM) plasma fluoride concentrations (umol litre"1) before and after sedation with isoflurane ( • ) or midazolam (El). FIG.
whom received isoflurane and 20 midazolam. Twenty-one patients sedated with isoflurane and 16 of those sedated with midazolam had received a volatile agent during surgery before entry to the study. The interval between the end of the anaesthetic and start of the study ranged from 45 min to 3 h in these patients. The two groups of patients were comparable in sex distribution, age, weight, APACHE II score and duration of study. Patients who received isoflurane for sedation showed a continuous increase in plasma F", whereas there was no significant change in plasma F" in those patients who received midazolam (fig. 1). More frequent blood samplings and measurements of plasma F" in those later patients who received isoflurane revealed that maximum plasma F" (13.57 |xmol litre"1) occurred 12 h after discontinuing isoflurane (fig. 2). The mean (range) dose of isoflurane used for sedation was 2.84 (1.14-6.38) MAC hours or 2.99 (1.2-6.7) vol% hours. In five of these patients, blood samples taken 48 h after discontinuation of isoflurane showed that, although plasma F" had declined
15
TABLE I. Details of patients studied. Mean {SEM)
Sex(M:F) Age (yr) Weight (kg) APACHE II score Duration of sedation (h) Admission diagnosis Postoperative surgical Others
Isoflurane group (« = 26)
Midazolam group (n = 20)
17:9 66.2(2.1) 63.3 (2.2) 14.7 (1.3) 18.2 (1.0)
18:2 65.5 (2.9) 70.5 (2.4) 14.4(1.5) 18.3(1.0)
24 2
17 3
5H
Baseline
End of sedation
4h
12h 24h After sedation
48 h
FIG. 2. Mean (SEM) plasma fluoride concentrations before and after isoflurane sedation. * = Series 1 (n = 14); • = series 2 (n = 5).
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
later that this frequency of sampling was inadequate in those patients receiving isofiurane sedation, and additional blood samples were taken at 4 and 12 h after discontinuing the trial sedative in subsequent patients who received isoflurane for sedation. In five of these patients further samples were taken also at 48 h after stopping isoflurane sedation. The plasma was separated, frozen and, subsequently, ionic F~ concentrations determined by direct ion-selective potentiometry using a fluoride-glass pH electrode system [2, 3]. Interassay coefficients of variation were 2.2% and 1.3% at mean plasma F~ concentrations of 2.0 ^mol litre"1 and 30 \imol litre"1, respectively. The lower limit for fluoride determination was 0.1 (xmol litre"1, with linearity from the lower limit of detection to 90 nmol litre"1 (linear correlation coefficient, r = 0.999). Care was taken to avoid fluoride contamination. Arterial blood samples were taken also at baseline, at the end of the period of trial sedation and 24 h after sedation for measurement of serum electrolytes, urea and creatinine concentrations. Hourly urine output was recorded. Nominal data were analysed by the Chi square test; for other data which could be assumed to be distributed normally, paired and unpaired t tests were used to compare means within and between groups, respectively; otherwise, the MannWhitney U test was used.
ISOFLURANE SEDATION
161
TABLE II. Mean (SEM) serum electrolyte, urea and creatinine concentrations before and after sedation with isoflurane or midazolam. * Significant difference from baseline (P < 0.05)
24 h after sedation
Isoflurane group (n = 26) Sodium (mmol litre"1) Potassium (mmol litre"1) Chloride (mmol litre"1) Bicarbonate (mmol litre"1) Urea (mmol litre"1) Creatinine (umol litre"1) Midazolam group (n = 20) Sodium (mmol litre"1) Potassium (mmol litre"1) Chloride (mmol litre"1) Bicarbonate (mmol litre"1) Urea (mmol litre"1) Creatinine (umol litre"1)
139.5 (0.8) 4.3 (0.2) 102.6(1.0) 24.1 (0.7) 9.2(1.0) 122.4(13.1)
139.6(1.1) 4.1 (0.2) 102.7(1.1) 24.8 (0.8) 11.5(1.3)* 147 (18.7)*
139.1 (1.2) 3.8(0.1) 102(1.1) 25.4 (0.9) 13(1.8)* 156.8 (26.2)
139.2(1.1) 4.4 (0.2) 101 (1.6) 25.6(1.6) 9.7(1.2) 139.6(16.2)
139.7 (1.2) 4.1 (0.1) 101.3(1.3) 27 (1.2) 11.7(1.3)* 155 (22.2)
140 (1.0) 3.7 (0.2) 100.1 (1.4) 27.8(1.1) 12.1 (1.6) 158.1 (27.1)
mean peak values of about 4.4 umol litre"1 from preoperative baseline values of 2.2 umol litre"1 [8]. Slightly greater peak serum F" concentrations (6.5 umol litre"1) were reported in morbidly obese patients exposed to 2.5 MAC hours of isoflurane [9]. We have used subanaesthetic concentrations of isoflurane (0.1-0.6 %) over much longer periods (mean duration 18.2 h). In our group of patients undergoing ventilation the metabolism of isoflurane may have been increased or altered by factors such as changes in hepatic blood flow, hypoxaemia, drugs (especially enzyme inducing drugs), genetic variation and concurrent illnesses. Compared with the above studies we found a greater mean maximum plasma fluoride concentration (13.57 umol litre"1) following sedation with a mean dose of 2.84 MAC hours isoflurane (2.99 vol% hours). However, this plasma F~ is DISCUSSION still far below that (50 umol litre"1) which has Metabolism of methoxyflurane to F~ was shown been reported to cause subclinical nephrotoxicity to result in dose-related, polyuric renal in- [10]. The majority of our patients were postsufficiency in man [4]. As a result of these studies, operative surgical patients, many of whom had methoxyflurane was withdrawn from human use. received an anaesthetic with a volatile agent before The extent of enflurane biotransformation to F" is entry to the study. We were unable to determine insufficient to result in clinically significant nephro- the effect of this exposure on the maximum toxicity [5], even in patients with pre-existing increase in plasma F". This maximum occurred renal insufficiency [6]. As only 0.2% of an 12 h after stopping isoflurane, later than the 6 h absorbed dose of isoflurane is biotransformed [7], after the end of an isoflurane anaesthetic reported F" nephrotoxicity appears unlikely. Studies in by Mazze, Cousins and Barr [8], but similar to man have shown that, following exposure to 3.1 that seen in morbidly obese patients [9]. Plasma MAC hours of isoflurane during surgical pro- F" in our patients were still increased 48 h after cedures lasting 2-7.5 h, serum F~ increased to stopping isoflurane sedation. We were unable to considerably, they were still increased above normal values (fig. 2). There were no significant differences in serum sodium, potassium, chloride and bicarbonate concentrations from baseline values in the two groups (table II). Serum urea and creatinine concentrations measured at the end of the study period and 24 h later were higher than baseline values in the two groups of patients, but there were no differences in urea or creatinine concentrations between the isoflurane and midazolam groups during the study period. Hourly urine outputs in both groups were within normal limits, and there was no difference in mean (SEM) hourly urine output during the study: 73.4 (7.5) ml h"1 compared with 79.6 (9.3) ml h"1, respectively.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
End of sedation
Baseline
162
REFERENCES 1. Kong KL, Willatts SM, Prys-Roberts C. Isoflurane compared with midazolam for sedation in the intensive
therapy unit. British Medical Journal 1989; 298: 12771280. 2. Tyler JE, Comer JEA. Novel ion-selective electrode system for the simultaneous determination offluorideand calcium in acid solution. Analyst 1985; 110: 15-18. 3. Tyler JE, Poole DFG, Kong KL. Determination of fluoride levels in blood plasma. Journal of Dental Research 1988; 67: 677. 4. Mazze RI, Trudell JR, Cousins MJ. Methoxyfturane metabolism and renal dysfunction: Clinical correlation in man. Anesthesiology 1971; 35: 247-252. 5. Mazze RI, Calverley RK, Smith NJ. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 1977; 46: 265-271. 6. Mazze RI, Sievenpiper TS, Stevenson J. Renal effects of enflurane and halothane in patients with abnormal renal function. Anesthesiology 1984; 60: 161-163. 7. Holaday DA, Fiserova-Bergerova V, Latto IP, Zumbiel MA. Resistance of isoflurane to biotransformation in man. Anesthesiology 1975; 43: 325-332. 8. Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536-542. 9. Strube PJ, Hulands GH, Halsey MJ. Serum fluoride levels in morbidly obese patients: enflurane compared with isoflurane anaesthesia. Anaesthesia 1987; 42: 685689. 10. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose response in man. Journal of the American Medical Association 1973; 225: 1611-1616.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
demonstrate any relationship between MAC hours or vol% hours of isoflurane used and maximum plasma F~. Hourly urine output in both groups was similar and not excessive. However, urinary concentrating ability, the most sensitive indicator of F~ nephropathy, was not measured. Both groups demonstrated increases in serum urea and creatinine concentrations from baseline values following isoflurane or midazolam sedation and are, therefore, unlikely to be related to increases in plasma F~. These increases in serum urea and creatinine concentrations could be accounted for by the general clinical condition of this group of patients receiving intensive therapy. Although the results of this study show that, after isoflurane sedation of up to 24 h, metabolism to F" is of insufficient magnitude to cause clinical renal dysfunction, further studies to exclude possible adverse effects of prolonged sedation are warranted.
BRITISH JOURNAL OF ANAESTHESIA
ISOFLURANE SEDATION FOR PATIENTS UNDERGOING MECHANICAL VENTILATION: METABOLISM TO INORGANIC FLUORIDE AND RENAL EFFECTS K. L. KONG, J. E. TYLER, S. M. WILLATTS AND C. PRYS-ROBERTS
We have shown that subanaesthetic concentrations of isoflurane (0.1-0.6%) provide a useful alternative technique for sedation of patients undergoing ventilation in the ITU [1]. Many critically ill patients may be expected to be receiving drug treatment which could result in hepatic enzyme induction. The metabolism of isoflurane to inorganic fluoride (F~) and its renal effects in these patients were therefore studied. PATIENTS AND METHODS
We studied 60 patients who required mechanical ventilation in the ITU. Patients were excluded if
Arterial blood samples were collected for measurement of plasma F~ at baseline, at the end of the period of trial sedation, and at 24 h after discontinuing the trial sedative. It was realized K.L.KONG*, M.B.B.S., F.F.A.R.C.S; S. M. WILLATTS, F.F.A.R.C.S., F.R.C.P.; C. PRYS-ROBERTS, M.A., D.M., PH.D., F.F.A.R.C.S., F.F.A.R.A.C.S., Sir Humphry Davy Department of
Anaesthesia, Bristol Royal Infirmary, Bristol BS2 8HW. J. E. TYLER, M.SC, PH.D., F.R.S.C, Medical Research Council
Dental Group, The Dental School, Lower Maudlin Street, Bristol BS1 2LY. Accepted for Publication: July 26, 1989. •Present address for correspondence: University Department of Anaesthesia, Queen Elizabeth Hospital, Birmingham B15 2TH.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
they were pregnant, had head injury or were in coma, were already under an established scheme The metabolism and renal effects of isoflurane of sedation, had a history of allergic response to sedation were studied for 24 h in patients morphine or benzodiazepines, were grossly obese undergoing mechanical ventilation. Forty-six or had uncontrolled haemorrhage. The study was patients admitted to our intensive therapy unit approved by the Bristol and Weston District were allocated randomly to receive either Ethics Committee. Informed consent for par0.1-0.6% isoflurane or midazolam 0.01-0.2 mg ticipation was obtained either from the patient or kg-1 / r ' for sedation. In 26 patients sedated with from the next of kin. Patients were allocated isoflurane, plasma inorganic fluoride increased randomly to receive either 0.1-0.6% isoflurane in i.v. from a mean concentration of 4.03 fimollitre'1 to an air-oxygen mixture or a continuous 1 1 infusion of midazolam 0.01-0.2 mg kg" h" for 13.57 fimol litre-' 12 h after stopping sedation. sedation. In those patients who received isoflurane Plasma inorganic fluoride concentrations in 20 patients sedated with midazolam were un- for sedation, end-tidal concentrations of the agent changed from baseline values (mean 5.32 txmol were measured with a Siemens Gas Monitor and litre-'). Serum electrolyte, urea and creatinine MAC hours of isoflurane calculated. By definition, concentrations, and urine output rates during MAC is not directly applicable to sedated patients and after sedation in patients who received and the end-tidal concentrations and duration of isoflurane were similar to those who received sedation were used to calculate the "volume per midazolam. We conclude that, following iso- cent hours " of isoflurane in each patient. The dose flurane sedation for up to 24 h, metabolism to of sedative was adjusted to maintain a desired inorganic fluoride is insufficient to cause clinical degree of sedation for as long as possible. The trial sedative was stopped either when the patient was renal dysfunction. judged ready for weaning from ventilatory support, or at 24 h (whichever was earlier). If sedation KEY WORDS was required beyond 24 h, an alternative scheme Anaesthetics inhalation: isoflurane. Intensive care: sedation. Metabolism: fluoride. of sedation was substituted. SUMMARY
BRITISH JOURNAL OF ANAESTHESIA
160
RESULTS
Of the 60 patients studied, results from 14 patients were incomplete either because they died during the study or because they had to return to theatre before blood sampling was completed. Results from the remaining 46 patients were analysed. Table I shows the details of these patients, 26 of
Before sedation
End of sedation
24 h after sedation
1 . Mean (SEM) plasma fluoride concentrations (umol litre"1) before and after sedation with isoflurane ( • ) or midazolam (El). FIG.
whom received isoflurane and 20 midazolam. Twenty-one patients sedated with isoflurane and 16 of those sedated with midazolam had received a volatile agent during surgery before entry to the study. The interval between the end of the anaesthetic and start of the study ranged from 45 min to 3 h in these patients. The two groups of patients were comparable in sex distribution, age, weight, APACHE II score and duration of study. Patients who received isoflurane for sedation showed a continuous increase in plasma F", whereas there was no significant change in plasma F" in those patients who received midazolam (fig. 1). More frequent blood samplings and measurements of plasma F" in those later patients who received isoflurane revealed that maximum plasma F" (13.57 |xmol litre"1) occurred 12 h after discontinuing isoflurane (fig. 2). The mean (range) dose of isoflurane used for sedation was 2.84 (1.14-6.38) MAC hours or 2.99 (1.2-6.7) vol% hours. In five of these patients, blood samples taken 48 h after discontinuation of isoflurane showed that, although plasma F" had declined
15
TABLE I. Details of patients studied. Mean {SEM)
Sex(M:F) Age (yr) Weight (kg) APACHE II score Duration of sedation (h) Admission diagnosis Postoperative surgical Others
Isoflurane group (« = 26)
Midazolam group (n = 20)
17:9 66.2(2.1) 63.3 (2.2) 14.7 (1.3) 18.2 (1.0)
18:2 65.5 (2.9) 70.5 (2.4) 14.4(1.5) 18.3(1.0)
24 2
17 3
5H
Baseline
End of sedation
4h
12h 24h After sedation
48 h
FIG. 2. Mean (SEM) plasma fluoride concentrations before and after isoflurane sedation. * = Series 1 (n = 14); • = series 2 (n = 5).
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
later that this frequency of sampling was inadequate in those patients receiving isofiurane sedation, and additional blood samples were taken at 4 and 12 h after discontinuing the trial sedative in subsequent patients who received isoflurane for sedation. In five of these patients further samples were taken also at 48 h after stopping isoflurane sedation. The plasma was separated, frozen and, subsequently, ionic F~ concentrations determined by direct ion-selective potentiometry using a fluoride-glass pH electrode system [2, 3]. Interassay coefficients of variation were 2.2% and 1.3% at mean plasma F~ concentrations of 2.0 ^mol litre"1 and 30 \imol litre"1, respectively. The lower limit for fluoride determination was 0.1 (xmol litre"1, with linearity from the lower limit of detection to 90 nmol litre"1 (linear correlation coefficient, r = 0.999). Care was taken to avoid fluoride contamination. Arterial blood samples were taken also at baseline, at the end of the period of trial sedation and 24 h after sedation for measurement of serum electrolytes, urea and creatinine concentrations. Hourly urine output was recorded. Nominal data were analysed by the Chi square test; for other data which could be assumed to be distributed normally, paired and unpaired t tests were used to compare means within and between groups, respectively; otherwise, the MannWhitney U test was used.
ISOFLURANE SEDATION
161
TABLE II. Mean (SEM) serum electrolyte, urea and creatinine concentrations before and after sedation with isoflurane or midazolam. * Significant difference from baseline (P < 0.05)
24 h after sedation
Isoflurane group (n = 26) Sodium (mmol litre"1) Potassium (mmol litre"1) Chloride (mmol litre"1) Bicarbonate (mmol litre"1) Urea (mmol litre"1) Creatinine (umol litre"1) Midazolam group (n = 20) Sodium (mmol litre"1) Potassium (mmol litre"1) Chloride (mmol litre"1) Bicarbonate (mmol litre"1) Urea (mmol litre"1) Creatinine (umol litre"1)
139.5 (0.8) 4.3 (0.2) 102.6(1.0) 24.1 (0.7) 9.2(1.0) 122.4(13.1)
139.6(1.1) 4.1 (0.2) 102.7(1.1) 24.8 (0.8) 11.5(1.3)* 147 (18.7)*
139.1 (1.2) 3.8(0.1) 102(1.1) 25.4 (0.9) 13(1.8)* 156.8 (26.2)
139.2(1.1) 4.4 (0.2) 101 (1.6) 25.6(1.6) 9.7(1.2) 139.6(16.2)
139.7 (1.2) 4.1 (0.1) 101.3(1.3) 27 (1.2) 11.7(1.3)* 155 (22.2)
140 (1.0) 3.7 (0.2) 100.1 (1.4) 27.8(1.1) 12.1 (1.6) 158.1 (27.1)
mean peak values of about 4.4 umol litre"1 from preoperative baseline values of 2.2 umol litre"1 [8]. Slightly greater peak serum F" concentrations (6.5 umol litre"1) were reported in morbidly obese patients exposed to 2.5 MAC hours of isoflurane [9]. We have used subanaesthetic concentrations of isoflurane (0.1-0.6 %) over much longer periods (mean duration 18.2 h). In our group of patients undergoing ventilation the metabolism of isoflurane may have been increased or altered by factors such as changes in hepatic blood flow, hypoxaemia, drugs (especially enzyme inducing drugs), genetic variation and concurrent illnesses. Compared with the above studies we found a greater mean maximum plasma fluoride concentration (13.57 umol litre"1) following sedation with a mean dose of 2.84 MAC hours isoflurane (2.99 vol% hours). However, this plasma F~ is DISCUSSION still far below that (50 umol litre"1) which has Metabolism of methoxyflurane to F~ was shown been reported to cause subclinical nephrotoxicity to result in dose-related, polyuric renal in- [10]. The majority of our patients were postsufficiency in man [4]. As a result of these studies, operative surgical patients, many of whom had methoxyflurane was withdrawn from human use. received an anaesthetic with a volatile agent before The extent of enflurane biotransformation to F" is entry to the study. We were unable to determine insufficient to result in clinically significant nephro- the effect of this exposure on the maximum toxicity [5], even in patients with pre-existing increase in plasma F". This maximum occurred renal insufficiency [6]. As only 0.2% of an 12 h after stopping isoflurane, later than the 6 h absorbed dose of isoflurane is biotransformed [7], after the end of an isoflurane anaesthetic reported F" nephrotoxicity appears unlikely. Studies in by Mazze, Cousins and Barr [8], but similar to man have shown that, following exposure to 3.1 that seen in morbidly obese patients [9]. Plasma MAC hours of isoflurane during surgical pro- F" in our patients were still increased 48 h after cedures lasting 2-7.5 h, serum F~ increased to stopping isoflurane sedation. We were unable to considerably, they were still increased above normal values (fig. 2). There were no significant differences in serum sodium, potassium, chloride and bicarbonate concentrations from baseline values in the two groups (table II). Serum urea and creatinine concentrations measured at the end of the study period and 24 h later were higher than baseline values in the two groups of patients, but there were no differences in urea or creatinine concentrations between the isoflurane and midazolam groups during the study period. Hourly urine outputs in both groups were within normal limits, and there was no difference in mean (SEM) hourly urine output during the study: 73.4 (7.5) ml h"1 compared with 79.6 (9.3) ml h"1, respectively.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
End of sedation
Baseline
162
REFERENCES 1. Kong KL, Willatts SM, Prys-Roberts C. Isoflurane compared with midazolam for sedation in the intensive
therapy unit. British Medical Journal 1989; 298: 12771280. 2. Tyler JE, Comer JEA. Novel ion-selective electrode system for the simultaneous determination offluorideand calcium in acid solution. Analyst 1985; 110: 15-18. 3. Tyler JE, Poole DFG, Kong KL. Determination of fluoride levels in blood plasma. Journal of Dental Research 1988; 67: 677. 4. Mazze RI, Trudell JR, Cousins MJ. Methoxyfturane metabolism and renal dysfunction: Clinical correlation in man. Anesthesiology 1971; 35: 247-252. 5. Mazze RI, Calverley RK, Smith NJ. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 1977; 46: 265-271. 6. Mazze RI, Sievenpiper TS, Stevenson J. Renal effects of enflurane and halothane in patients with abnormal renal function. Anesthesiology 1984; 60: 161-163. 7. Holaday DA, Fiserova-Bergerova V, Latto IP, Zumbiel MA. Resistance of isoflurane to biotransformation in man. Anesthesiology 1975; 43: 325-332. 8. Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536-542. 9. Strube PJ, Hulands GH, Halsey MJ. Serum fluoride levels in morbidly obese patients: enflurane compared with isoflurane anaesthesia. Anaesthesia 1987; 42: 685689. 10. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose response in man. Journal of the American Medical Association 1973; 225: 1611-1616.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on July 7, 2015
demonstrate any relationship between MAC hours or vol% hours of isoflurane used and maximum plasma F~. Hourly urine output in both groups was similar and not excessive. However, urinary concentrating ability, the most sensitive indicator of F~ nephropathy, was not measured. Both groups demonstrated increases in serum urea and creatinine concentrations from baseline values following isoflurane or midazolam sedation and are, therefore, unlikely to be related to increases in plasma F~. These increases in serum urea and creatinine concentrations could be accounted for by the general clinical condition of this group of patients receiving intensive therapy. Although the results of this study show that, after isoflurane sedation of up to 24 h, metabolism to F" is of insufficient magnitude to cause clinical renal dysfunction, further studies to exclude possible adverse effects of prolonged sedation are warranted.
BRITISH JOURNAL OF ANAESTHESIA
