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Anesthesia for craniotomy: Total intravenous anesthesia with propofol and alfentanil compared to anesthesia with thiopental sodium, isoflurane, fentanyl, and nitrous oxide
Anesthesia for Craniotomy: Total Intravenous Anesthesia with Propofol and Alfentanil Compared to Anesthesia with Thiopental Sodium, Isof lurane, Fentanyl, and Nitrous Oxide Jan Van Hemelrijck, MD,* Hugo Van Aken, MD,? Luc Merckx, MD& Jan Mulier, MD5 1)epartment
of Anesthesiology,
Study Objective:
Katholieke
Universiteit Leuven, Belgium.
To compare a total intravenous (IV) anesthetic tech18@e bused
on propofol and alfentanil with a commons used unesthetic technique ftir craniotomy. Design:
Open-label, mndomized, clinical study.
Setting:
Neurosuqgical clinic at a university hospital.
Patients: Forty patients, aged I8 to 55 years, scheduled ,for bruin tum’or surgery. Interventions: In 20 patients, anesthesia was induced with .f&tanyi! and thiopental sodium and maintained with fentanyl, dehydrobenzperidol, *Staff
Member
tProfessor
a11d Chairman
$Kesident
trous oxide (N,O),
and a thiopental sodium infusion.
isof?urane, ni-
Twenty patients were
ccnesthetized with a profiofol loading infusion followed by u maintenance infusion at u fixed rate. In addition, alfentanil was administered us a loading bolus, followed by a aariable-rate infusion, with additional doses as necessary to maintain hemodynumic stability. Measurements and Main Results: A decrease in blood pressure (BP) after induction with thiopental sodium was followed by a significant increase in BP and
Address reprint requests to Dr. Van Aken at the Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, B3W.M Leuven, Belgium. Received fbr publication January 31, 1990; revised manuscript accepted for publication August 7, 1990. 0 199 1 Butterworth-Heinemann
hemt rate (HR) during intubation. BP and HR did not change during the propqfol loading infusion. However, the administration of alfentanil was followed by a similar decrease in BP with a return to bnseline uulues during the intubation period. Return of normal orientation (7 f
5 minutes vs 27 i
23 minutes) and
concentration (12 * 12 minutes vs 35 2 37 minutes) was shorter and more predictable for tlle p rop of o l- a Ifen tanil-treated patients than,for the thiopental sodium patients. Maintenance propofol concentration (nine patient.c) was between 3 * 0.69 kglml and 3.36 * 1 .I7 pglml, while the concentration at #awakening was 1.09 bglml. Alfentanil concentration at extubation (nine patients) was 79 -+ 34 nglml. J. Clin. Anesth., vol. 3, March/April 1991
131
Original Contributions Conclusion:
A total IV anesthetic technique with propofol
and alfentanil is a valuable alternative to a more commonly used technique based on thiopental sodium, N,O, fentanyl, and isoflurane.
Keywords: anesthetics;
Neuroanesthesia; intravenous propofol; alfentanil; anesthesia.
Introduction Intraoperative hemodynamic stability and early and complete recovery, allowing for postoperative neurologic assessment, often are required for neurosurgical interventions. Cerebral autoregulation and the coupling of cerebral metabolism and blood flow should be unaltered.’ These goals are difficult to achieve with techniques based on volatile anesthetics. Cerebral autoregulation is preserved only with isoflurane at low concentrations.” Higher concentrations of all volatile anesthetics impair the autoregulatory response to BP changes.2.J Opinions as to the place of N,O in neuroanesthesia remain divided. N,O is a cerebral metabolic stimulant causing an increase in cerebral blood flo~,~-~ although these effects can be obtunded by other anesthetics.x Most IV anesthetics cause a coupled reduction in cerebral metabolism and blood flow. However, the usefulness of total IV anesthetic techniques has been limited by the pharmacokinetic properties of most available hypnotics, causing prolonged awakening times. Etomidate has been used successfully for a total IV anesthetic technique in neuroanesthesia,” but its effect on cortisol synthesis has discredited its use for prolonged infusions. The relative short metabolic half-life of propofol (2 to 4 hours) makes the drug suitable for use as the primary hypnotic for total IV anesthesia.“‘~‘” Its effects on cerebral metabolism and blood flow are similar to those of thiopental sodium.14+‘” Propofol does not impair cerebral autoregulation in normal primates. I6 These considerations prompted the authors to use a total IV anesthetic technique based on propofol and alfentanil without N,O for craniotomies. The purpose of this study was to compare the hemodynamic stability and recovery characteristics of the authors’ new approach to a commonly used technique based on thiopental sodium, fentanyl, isoflurane, and N,O. Additionally, blood propofol and plasma alfentanil concentrations were determined in nine patients.
Materials and Methods The study was approved by the Ethical Committee of the Faculty of Medicine of the Katholieke Universiteit 132
J. Clin. Anesth., vol. 3, March/April 1991
Leuven. Forty consenting patients, aged 18 to 55 years, who were scheduled for brain tumor surgery were studied. CardiovascuIar, liver, and renal disease; hypertension; diabetes; pregnancy; and gross obesity (more than 15% overweight) were exclusion criteria. All patients received corticosteroid therapy and phenobarbital for at least 5 days preoperatively. The patients were randomly assigned to one of two groups. Twenty patients were anesthetized with a commonly used technique. For induction, fentanyl 1.5 rJ_gi kg was followed 4 minutes later by thiopental sodium 4 to 6 mgikg and pancuronium 0.1 mg/kg. Intubation followed 3 minutes later. Anesthesia was maintained with fentanyl (8 to 10 pg/kg by intermittent bolus administration), dehydrobenzperidol (100 pg/kg at the moment of incision), isoflurane [maximally 1 minimum alveolar concentration (MAC)], 70% N,O, and a thiopental sodium infusion (2 mg/kg/h to improve brain relaxation). The thiopental sodium infusion was stopped at the beginning of dura mater closure. Twenty patients were assigned to the total IV anesthesia group. A loading infusion of propofol at a dose of 2 1 mg/kg/h was given for 5 minutes, followed by a reduced infusion dosage of 12 mg/kg/h for 10 minutes. Seven minutes after the start of the propofol infusion, 25 pg/kg of alfentanil and 0.1 mg/kg of pancuronium were administered, followed by an endotracheal intubation 3 minutes later. Maintenance of anesthesia was provided by a continuous infusion of propofol of 6 mglkgih until skin closure. For analgesia, alfentanil was infused at the rate of 100 pgikgi h until the dura mater was opened and then at 25 to 100 pgikglh, adjusted to maintain hemodynamic stability, until the start of dura closure. Additional 20 pgikg boluses of alfentanil were administered if signs of inadequate analgesia were present [HR or mean arterial pressure (MAP) >20% higher than baseline values]. The patients were ventilated with air and oxygen (0,). End-tidal carbon dioxide (P,,CO,) was measured continuously (Normocap, Datex, Helsinki, Finland). Normocapnia was maintained until intubation, if necessary, by prompting the patient to take deep breaths or by manual ventilation, as appropriate. After intubation, mechanical ventilation was initiated and adjusted to maintain a P&O, of 28 to 32 mmHg. Before extubation, adequate neuromuscular transmission was assessed by nerve stimulation, and if necessary, pancuronium was reversed with neostigmine. The ability to maintain adequate spontaneous ventilation was assessed by capnography. A radial artery was cannulated before induction, and BP was measured continuously. The transducer was zero-referenced to the external auditory meatus.
BP and HR were recorded every minute for the first 20 minutes of anesthesia. Recovery was assessed by three standardized tests: (1) orientation to place, name, and day of the week; (2) concentration ability, evaluated by a countdown test (count down from 40 to 30); and (3) short memory, tested by the ability to recall the location of four black spots in a nine-square maze (shown for 30 seconds). The testing was performed by one of the authors, who was blinded to the treatment group. Immediately preoperatively, all patients were able to perform the tests without hesitation. The times from responding to commands to correct performance of the orientation, concentration, and short-memory tests were noted. The concentration test was performed every 5 minutes and the short-memory test every 15 minutes. Two patients in the total IV anesthesia group were unable to perform the short-memory test due to postoperative visual disturbance of surgical origin and were not included in the analysis for this test. In nine patients from the total IV anesthesia group, propofol (heparinized blood) and alfentanil (frozen plasma) concentrations were measured at predefined times: 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes after induction of anesthesia, at the moment of stopping the propofol infusion, and when the patients responded to simple commands. Arterial blood samples were collected in tubes that contained potassium oxalate. After thorough mixing, they were cooled to 4°C and stored at this temperature until analysis for blood propofol content using highperformance liquid chromatography with fluorescence detection, as previously described” (ICI Pharmaceuticals Division, Macclesfield, UK). Arterial blood samples were centrifuged, and the plasma was frozen at -20°C for analysis of alfentanil content using gas chromatographyI I (Janssen Research Foundation, Beerse, Belgium). All measurements are presented as means ? SD. Hemodynamic data were analyzed by Friedman’s test for changes over time within each group and by analysis of variance for between-group differences. The recovery data were analyzed with the Mann-Whitney rank test; p < 0.05 was considered significant.
Results There were no differences in age (45 -+ 3 years for the thiopental sodium group us 45 t 4 years for the propofol-alfentanil group), sex distribution (male/female 1218 for the thiopental sodium group us 1 l/9 for the propofol-alfentanil group), or operation time (293
ir 106 minutes for the thiopental sodium group us 270 * 102 minutes for the propofol-alfentanil group). The hemodynamic data during the induction and I. There was intubation sequence are shown in Figwe no difference between baseline BP and HR between
. Propofolo Thlopental-
Alfentanii Fentanyl-
2oor
isotiurane
- N,O
x
rl-
150
5011_130
C
beats
HR per
min.
‘1
T
Ii.;-r.;__~_~
‘O
m-T1
50 I____-, I * different x difference xx ~~005
I2
3
4
5
6
7
from baseline between groups
Figure 1. Hetnodynm~ic
profiles of two gro~lps of patients fdlowing inciuctiott of’ anesthesia with thiopetttal sodium: fentattyl, isoflurane, and nitrous oxide (ITlO) (0) ancl a total IV anesthetic technique with propofol and alfkntanil (0). ILila are means 2 SD. (1 = lmseline; 2 = 1 minute after fknrattvl in the rhiopental sodium group or after 4 tttinutes loatlin~ infusion of propofi~l; 3 = 1 minute al’ter Ihiopental sotliuttt or 1 minute af‘ter altentattil; 4 = during itttubation; 5 = 1 minute after intubation; 6 = 5 minutes after intub~ition: 7 = IO minutes after intulmtion; SAP = systolic at~terial pressure; 1)AP = diastolic arterial pressure; MAP = mean at-terial pressure; HR = heart rale.)
J. Clin. Anesth.,
vol. 3, March/Aptd
19911
133
Contributions
(higir~ul
the groups. A decrease in systolic arterial pressure (SAP) (fi-om 140 +- 19 mmHg to 111 1 17 mmHg) and in MAP (from 97 + 14 mmHg to 75 i- 8 mmHg) occurred 1 minute after thiopental sodium administration. Significant increases in HR (from 82 t 20 beats/minute to 107 2 18 beats/minute), SAP (to 17 1 t 11 mmHg), MAP (to 116 * 8 mmHg), and diastolic arterial pressure (DAP) (from 73 ? 12 mmHg to 94 t 10 mmHg) were noted during intubation in the thiopental sodium group. Hemodynamic parameters did not change during the 5-minute propofol loading infusion. However, BP decreased after the bolus administration of alfentanil (SAP decreased from 137 2 16 mmHg to 109 i 17 mmHg and MAP from 92 t 9 mmHg to 74 f 13 mmHg), returning to baseline during intubation and decreasing again 1 minute later. Nevertheless, BP in the total IV anesthesia group was never significantly different from that in the thiopental sodium group except during intubation, when BP as well as HR were higher in the thiopental sodium group. After the initial 20-minute study period, the BP profile was similar for both study groups, and hypotension (SAP <95 mmHg) was avoided in all patients. Figure 2 summarizes the recovery data. The times from awakening to correct orientation (7 2 5 minutes US 27 t 23 minutes) and to correct performance of the concentration test (12 t 12 minutes US 35 2 37 minutes) were shorter for patients anesthetized with the new technique. The absolute value of the SD was strikingly smaller for the total IV anesthesia group, indicating better predictability of early, more complete
recovery.
The
Effect of Anesthetic
time
to correct
technique
on
performance
the short-memory test did not differ (27 2 15 minutes for the propofol-alfentanil group UT37 2 17 minutes for the thiopental sodium group). No correlation was present between the duration of the propofol infusion (280 + 95 minutes) and the recovery test times. Blood concentrations of propofol for nine patients are shown in I;@NP 3. .l’he concentration reached 7.42 i 1.19 ygiml after the 5-minute loading infusion. After the first 30 minutes, the concentrations ranged from 3 ? 0.69 pgiml to 3.36 ? 1.17 kg/ml. The apparent steadystate concentration of propofol after the first 60 minutes of infusion was 3.14 t 0.78 kg/ml. The steadystate clearance (calculated as maintenance infusion/ mean blood concentration for time 60 minutes to the end of the infusion) was 2.254 f- 0.45 Limin. Patients woke up at 1.09 + 0.19 pgiml. FZgzlre 4 shows the variation in alfentanil plasma concentration. Since alfentanil administration was titrated to minimize the hemodynamic response to stimulation, a wide plasma concentration range was expected. The concentration varied between 128 ? 58 ng/ml and 252 ? 112 ngiml. At the moment of
Propofol blood
011 5
11
15 30
11
45
1
”
”
1
’
120 180 240 300STOP AWAKE infusion Time (minutes) 60
90
Figure 3. Blood concentration k SD.
Bo
lmean+S.D.i
Ior
of’
Behavior
concentration
of propofol.
Data are means
ALfentantlplasma concentration (mean+S.O.i
500
c
= E w
200-
2
100 0 0
Figure
2. Recovery
times for orientation, concentration, and short-memory tests. The times from the patients’ initial responses to commands to the correct performance of the tests are indicated. Data are means i SD. (N,O = nitrous oxide.)
134
J. Clin. Anesth.,
vol. 3, March/April
1991
5
15
30 45 60 90 Time [minutes)
Figure 4. Plasma concentration tients. Data are means t- SD.
120 180 STOP AWAKE infusion
of alfentanil
for nine
pa-
extubation, ml.
the plasma concentration
was 79 2 34 ngl
Discussion Carlier et ~1.~~’ described a decrease in BP on induction of anesthesia with propofol. This decrease in BP can lead to a dangerous reduction in cerebral perfusion pressure, especially in patients with reduced cerebral compliance.“’ In the present study, a reduction in BP was avoided by using a loading infusion instead of a bolus dose. Only after the addition of alfentanil did BP decrease significantly. The addition of alfentanil to a propofol infusion can cause an important decrease in BP, even in the presence of a drug with vagolytic properties such as pancuronium. Careful drug titration and close monitoring of its effects are therefore recommended. However, a similar decrease in BP occurred after thiopental sodium and fentanyl administration. Since intracranial pressure was not measured in this study, no exact statements can be made about the cerebral perfusion pressure. Furthermore, every effort was made to maintain normocapnia during the induction period to avoid an increase in intracranial pressure caused by an increased arterial partial pressure of CO, (PCO,), which could provoke further impairment of cerebral perfusion pressure. When autoregulation is disturbed or its limits exceeded, endotracheal intubation can cause marked cardiocirculatory responses leading to deleterious increases in cerebral blood flow.“-‘” In patients with reduced intracranial compliance, such BP increases may reduce cerebral perfusion pressure and cause furthel- cerebral impairment. In the propofol-alfentanil treated patients, the cardiocirculatory response to intubation was limited to a return to baseline. However, in the thiopental sodium-fentanyl treated patients, a significant increase in HR and BP occurred, indicating that the stress response to intubation was not sufficiently blocked by the dose of fentanyl used. Because it was difficult to define comparable end points of anesthesia in the two treatment groups, recovery times were determined from the moment the patients first responded to simple commands to correct performance of the different recovery tests. All patients woke up from anesthesia within a reasonable time after the end of surgery (0 to 40 minutes), but the recovery times for orientation and concentration tests were significantly shorter for the propofolalfentanil treated patients, with a smaller SD. This situation allows for a more complete early neurologic evaluation. The concentration of propofol (3 t 0.69 kg/ml to
3.36 % 1.17 pgiml) is similar to the concentration previously described for total IV anesthesia for nonmajor abdominal surgery” and for computer-conThe calculated steady-state trolled anesthesia.“.‘” clearance (2.254 k 0.45 Limin) was greater than the steady-state clearance calculated from data resulting from short infusions by Shafer ct 01.” (1.96 i- 0.57 to 2.08 ‘r_ 0.70 Limin), Gepts et ul.” (I..5 to 1.9 Limin), and Schiittler et aLy5 (1.9 ? 0.1 Limin). Whether this finding is due to differences in patient population (u.g., patients in this study were treated with anticonvulsant medication) or to the small sample size cannot be determined. The mean propofol blood concentration at awakening (1.09 i 0.19 ~gimlj is similar to previously reported values. ’‘x’ The large variation in alfentanil plasma concentration is the result of the adjustments of lthe alfentanil administration to the differing analgesic demands of the individual patients. Ausems et (~1.‘~described the variation of alfentanil plasma concentration needed to block reaction to different stimulus inl:ensities. The alfentanil concentration at the moment of awakening in the present study (79 i: 34 ngiml) is well below the reported limit for spontaneous respiration (223 ng/ml with a 95% confidence limit: 197 to 249 ngiml).” The present authors found no correlation between the duration of propofol administration and the recovery test times. ‘I‘his finding may indicate that the duration of propofol administration, within the time limits studied, does not influence recovery time. Alternatively, it may be explained by the predominant influence of the large doses of’alfentanil on recovery times. Alfentanil has been found to increase cerebrospinal fluid pressure in patients with brain tumors.2K Others have not found any changes in cerebral blood flow or metabolism with doses up to 150 Fg/kg in humans.” Nevertheless, operative conditions were excellent in all of the present study patients. Finally, a total IV anesthetic technique with propofol and alfentanil allowed the present authors to avoid the administration of N,O. Its use in neuroanesthesia is controversial because it is a potent direct cerebral vasodilator.d-7 Furthermore, since it has been shown that N,O in the presence of brain ischemia in rats can worsen neuronal injury, one should consider not using it during surgery in the presence of human brain ischemia.“” The authors conclude that total IV anesthesia with the combined use of propofol and alfentanil provides a safe alternative to an anesthetic technique based on thiopental sodium, fentanyl, low-dose isoflurane, and X,0. The total IV technique results in safer circulatory conditions during intubation and earlier, more complete, and more predictable recovery. In addition, the use of N,O is avoided. J. Clin. Anesth., bol. 3, MarchiApl-il
1991
135
Original
Contributions
References 1. Van Aken H: Neurosurgical anaesthesia and neurological disease. Editorial overview. Current Opinion in Anaesthesiology 1989;2:535-6. 2. Van Aken H, Fitch W, Graham DI, Briissel T, Themann H: Cardiovascular and cerebrovascular effects of isoflurane-induced hypotension in the baboon. An&h Analg 1986;65:565-74. 3. Miletich DJ, Ivankovich AD, Albrecht RF, Reimann CE, Rosenberg R, McKissic ED: Absence of autoregulation of cerebral blood flow during halothane and enflurane anesthesia. An&h Analg 1976;55:100-9. 4. Sakabe T, Kuramoto T, Inoue S, Takeshita H: Cerebral effects of nitrous oxide in the dog. Anesthesiology 1978; 48: 195-200. 5. Oshita S, Ishikawa T, Tokutsu Y, Takeshita H: Cerebral circulatory and metabolic stimulation with nitrous oxide in the dog. Acta Anaesthesiol Stand 1978;23: 17781. 6. Pelligrino D, Miletich DJ, Hoffmann WE, Albrecht RF: Nitrous oxide markedly increases cerebral metabolic 1984; rate and blood flow in the goat. Anesthesiolog?l 60:405-19. 7. Hansen TD, Warner DS, Todd MM: Nitrous oxide is a more potent cerebral vasodilator than either halothane or isoflurane. AnesthesioloLgy 1988;69:537-43. 8. Shapiro HM: Modification of nitrous oxide induced intracranial hypertension by prior induction of anesthesia. Anesthesiology 1977;46: 150-l. 9. Sear JW, Walters FJM, Wilkins DC;, Willatts SM: Etomidate by infusion for neuroanaesthesia. Anaesthesia 1984;39:
12-8.
16
17.
18.
19.
20.
21.
22.
23.
24.
25.
10
Fragen RJ, Hansen EMH, Denissen PAF, Booij LHDJ, Crul JF: Disoprofol for total intravenous anaesthesia. Acta Anaesthesiol Stand 1983;27: 113-7. 11. Shafer A, Doze VA, Shafer SL, White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988;69:34856.
Schiittler J, Kloos S, Schwilden H, Stoeckel H: Total intravenous anaesthesia with propofol and alfentanil by computer-assisted infusion. Anaesthesia 1988;43 (Suppl): 2-7. 13. Tack;ey RM, Lewis GTR, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. BY J Anaesth 1989;62:46-53. 14. Vandesteene A, Trempont V, Engelman E, et al: Effect of propofol on cerebral blood flow and metabolism in man. Anaesthesia 1988;43(Suppl):42-3. 15. Stephan H, Sonntag H, Schenk HD, Kohlshausen S: Einfluss von Disoprivan (Propofol) auf die Durchblutung und den Sauerstoffverbrauch des Gehirns und die CO, Reaktivitat der Hirngefgsse beim Menschen [Effects of Disoprivan (propofol) on cerebral blood flow, cerebral oxygen consumption and cerebral vascular reactivity]. Anaesthesist 1987;36:60-5.
26.
27.
12.
136
J, Clin. Anesth., vol. 3, March/April 1991
28.
Van Hemelrijck J, Fitch W, Mattheussen M, Van Aken H, Plets C: The effect of propofol on the cerebral circulation and autoregulation in the baboon. Anesth Analg !990;71:49-54. Plummer GF: Improved method for the determination of propofol in blood by high-performance liquid chromatography with fluorescence detection. J Chromato
1:3-7. 29. Larsen R, Hilfiker 0: Alfentanil: Wirkungen auf Hirndurchblutung und Hirnstoffwechsel des Menschen (Alientanil: effects on cerebral blood flow and metabolism in humans). In Doenicke A, ed. AZfentanil. Berlin: Springer Verlag, 1986: 120-4. 30. Baughman VL, Hoffman WE, Thomas C, Albrecht RF, Miletich DJ: The interaction of nitrous oxide and isoflurane with incomplete cerebral ischemia in the rdt. Anesthesiology
1989;70:767-71.
of Anesthesiology,
Study Objective:
Katholieke
Universiteit Leuven, Belgium.
To compare a total intravenous (IV) anesthetic tech18@e bused
on propofol and alfentanil with a commons used unesthetic technique ftir craniotomy. Design:
Open-label, mndomized, clinical study.
Setting:
Neurosuqgical clinic at a university hospital.
Patients: Forty patients, aged I8 to 55 years, scheduled ,for bruin tum’or surgery. Interventions: In 20 patients, anesthesia was induced with .f&tanyi! and thiopental sodium and maintained with fentanyl, dehydrobenzperidol, *Staff
Member
tProfessor
a11d Chairman
$Kesident
trous oxide (N,O),
and a thiopental sodium infusion.
isof?urane, ni-
Twenty patients were
ccnesthetized with a profiofol loading infusion followed by u maintenance infusion at u fixed rate. In addition, alfentanil was administered us a loading bolus, followed by a aariable-rate infusion, with additional doses as necessary to maintain hemodynumic stability. Measurements and Main Results: A decrease in blood pressure (BP) after induction with thiopental sodium was followed by a significant increase in BP and
Address reprint requests to Dr. Van Aken at the Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, B3W.M Leuven, Belgium. Received fbr publication January 31, 1990; revised manuscript accepted for publication August 7, 1990. 0 199 1 Butterworth-Heinemann
hemt rate (HR) during intubation. BP and HR did not change during the propqfol loading infusion. However, the administration of alfentanil was followed by a similar decrease in BP with a return to bnseline uulues during the intubation period. Return of normal orientation (7 f
5 minutes vs 27 i
23 minutes) and
concentration (12 * 12 minutes vs 35 2 37 minutes) was shorter and more predictable for tlle p rop of o l- a Ifen tanil-treated patients than,for the thiopental sodium patients. Maintenance propofol concentration (nine patient.c) was between 3 * 0.69 kglml and 3.36 * 1 .I7 pglml, while the concentration at #awakening was 1.09 bglml. Alfentanil concentration at extubation (nine patients) was 79 -+ 34 nglml. J. Clin. Anesth., vol. 3, March/April 1991
131
Original Contributions Conclusion:
A total IV anesthetic technique with propofol
and alfentanil is a valuable alternative to a more commonly used technique based on thiopental sodium, N,O, fentanyl, and isoflurane.
Keywords: anesthetics;
Neuroanesthesia; intravenous propofol; alfentanil; anesthesia.
Introduction Intraoperative hemodynamic stability and early and complete recovery, allowing for postoperative neurologic assessment, often are required for neurosurgical interventions. Cerebral autoregulation and the coupling of cerebral metabolism and blood flow should be unaltered.’ These goals are difficult to achieve with techniques based on volatile anesthetics. Cerebral autoregulation is preserved only with isoflurane at low concentrations.” Higher concentrations of all volatile anesthetics impair the autoregulatory response to BP changes.2.J Opinions as to the place of N,O in neuroanesthesia remain divided. N,O is a cerebral metabolic stimulant causing an increase in cerebral blood flo~,~-~ although these effects can be obtunded by other anesthetics.x Most IV anesthetics cause a coupled reduction in cerebral metabolism and blood flow. However, the usefulness of total IV anesthetic techniques has been limited by the pharmacokinetic properties of most available hypnotics, causing prolonged awakening times. Etomidate has been used successfully for a total IV anesthetic technique in neuroanesthesia,” but its effect on cortisol synthesis has discredited its use for prolonged infusions. The relative short metabolic half-life of propofol (2 to 4 hours) makes the drug suitable for use as the primary hypnotic for total IV anesthesia.“‘~‘” Its effects on cerebral metabolism and blood flow are similar to those of thiopental sodium.14+‘” Propofol does not impair cerebral autoregulation in normal primates. I6 These considerations prompted the authors to use a total IV anesthetic technique based on propofol and alfentanil without N,O for craniotomies. The purpose of this study was to compare the hemodynamic stability and recovery characteristics of the authors’ new approach to a commonly used technique based on thiopental sodium, fentanyl, isoflurane, and N,O. Additionally, blood propofol and plasma alfentanil concentrations were determined in nine patients.
Materials and Methods The study was approved by the Ethical Committee of the Faculty of Medicine of the Katholieke Universiteit 132
J. Clin. Anesth., vol. 3, March/April 1991
Leuven. Forty consenting patients, aged 18 to 55 years, who were scheduled for brain tumor surgery were studied. CardiovascuIar, liver, and renal disease; hypertension; diabetes; pregnancy; and gross obesity (more than 15% overweight) were exclusion criteria. All patients received corticosteroid therapy and phenobarbital for at least 5 days preoperatively. The patients were randomly assigned to one of two groups. Twenty patients were anesthetized with a commonly used technique. For induction, fentanyl 1.5 rJ_gi kg was followed 4 minutes later by thiopental sodium 4 to 6 mgikg and pancuronium 0.1 mg/kg. Intubation followed 3 minutes later. Anesthesia was maintained with fentanyl (8 to 10 pg/kg by intermittent bolus administration), dehydrobenzperidol (100 pg/kg at the moment of incision), isoflurane [maximally 1 minimum alveolar concentration (MAC)], 70% N,O, and a thiopental sodium infusion (2 mg/kg/h to improve brain relaxation). The thiopental sodium infusion was stopped at the beginning of dura mater closure. Twenty patients were assigned to the total IV anesthesia group. A loading infusion of propofol at a dose of 2 1 mg/kg/h was given for 5 minutes, followed by a reduced infusion dosage of 12 mg/kg/h for 10 minutes. Seven minutes after the start of the propofol infusion, 25 pg/kg of alfentanil and 0.1 mg/kg of pancuronium were administered, followed by an endotracheal intubation 3 minutes later. Maintenance of anesthesia was provided by a continuous infusion of propofol of 6 mglkgih until skin closure. For analgesia, alfentanil was infused at the rate of 100 pgikgi h until the dura mater was opened and then at 25 to 100 pgikglh, adjusted to maintain hemodynamic stability, until the start of dura closure. Additional 20 pgikg boluses of alfentanil were administered if signs of inadequate analgesia were present [HR or mean arterial pressure (MAP) >20% higher than baseline values]. The patients were ventilated with air and oxygen (0,). End-tidal carbon dioxide (P,,CO,) was measured continuously (Normocap, Datex, Helsinki, Finland). Normocapnia was maintained until intubation, if necessary, by prompting the patient to take deep breaths or by manual ventilation, as appropriate. After intubation, mechanical ventilation was initiated and adjusted to maintain a P&O, of 28 to 32 mmHg. Before extubation, adequate neuromuscular transmission was assessed by nerve stimulation, and if necessary, pancuronium was reversed with neostigmine. The ability to maintain adequate spontaneous ventilation was assessed by capnography. A radial artery was cannulated before induction, and BP was measured continuously. The transducer was zero-referenced to the external auditory meatus.
BP and HR were recorded every minute for the first 20 minutes of anesthesia. Recovery was assessed by three standardized tests: (1) orientation to place, name, and day of the week; (2) concentration ability, evaluated by a countdown test (count down from 40 to 30); and (3) short memory, tested by the ability to recall the location of four black spots in a nine-square maze (shown for 30 seconds). The testing was performed by one of the authors, who was blinded to the treatment group. Immediately preoperatively, all patients were able to perform the tests without hesitation. The times from responding to commands to correct performance of the orientation, concentration, and short-memory tests were noted. The concentration test was performed every 5 minutes and the short-memory test every 15 minutes. Two patients in the total IV anesthesia group were unable to perform the short-memory test due to postoperative visual disturbance of surgical origin and were not included in the analysis for this test. In nine patients from the total IV anesthesia group, propofol (heparinized blood) and alfentanil (frozen plasma) concentrations were measured at predefined times: 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes after induction of anesthesia, at the moment of stopping the propofol infusion, and when the patients responded to simple commands. Arterial blood samples were collected in tubes that contained potassium oxalate. After thorough mixing, they were cooled to 4°C and stored at this temperature until analysis for blood propofol content using highperformance liquid chromatography with fluorescence detection, as previously described” (ICI Pharmaceuticals Division, Macclesfield, UK). Arterial blood samples were centrifuged, and the plasma was frozen at -20°C for analysis of alfentanil content using gas chromatographyI I (Janssen Research Foundation, Beerse, Belgium). All measurements are presented as means ? SD. Hemodynamic data were analyzed by Friedman’s test for changes over time within each group and by analysis of variance for between-group differences. The recovery data were analyzed with the Mann-Whitney rank test; p < 0.05 was considered significant.
Results There were no differences in age (45 -+ 3 years for the thiopental sodium group us 45 t 4 years for the propofol-alfentanil group), sex distribution (male/female 1218 for the thiopental sodium group us 1 l/9 for the propofol-alfentanil group), or operation time (293
ir 106 minutes for the thiopental sodium group us 270 * 102 minutes for the propofol-alfentanil group). The hemodynamic data during the induction and I. There was intubation sequence are shown in Figwe no difference between baseline BP and HR between
. Propofolo Thlopental-
Alfentanii Fentanyl-
2oor
isotiurane
- N,O
x
rl-
150
5011_130
C
beats
HR per
min.
‘1
T
Ii.;-r.;__~_~
‘O
m-T1
50 I____-, I * different x difference xx ~~005
I2
3
4
5
6
7
from baseline between groups
Figure 1. Hetnodynm~ic
profiles of two gro~lps of patients fdlowing inciuctiott of’ anesthesia with thiopetttal sodium: fentattyl, isoflurane, and nitrous oxide (ITlO) (0) ancl a total IV anesthetic technique with propofol and alfkntanil (0). ILila are means 2 SD. (1 = lmseline; 2 = 1 minute after fknrattvl in the rhiopental sodium group or after 4 tttinutes loatlin~ infusion of propofi~l; 3 = 1 minute al’ter Ihiopental sotliuttt or 1 minute af‘ter altentattil; 4 = during itttubation; 5 = 1 minute after intubation; 6 = 5 minutes after intub~ition: 7 = IO minutes after intulmtion; SAP = systolic at~terial pressure; 1)AP = diastolic arterial pressure; MAP = mean at-terial pressure; HR = heart rale.)
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the groups. A decrease in systolic arterial pressure (SAP) (fi-om 140 +- 19 mmHg to 111 1 17 mmHg) and in MAP (from 97 + 14 mmHg to 75 i- 8 mmHg) occurred 1 minute after thiopental sodium administration. Significant increases in HR (from 82 t 20 beats/minute to 107 2 18 beats/minute), SAP (to 17 1 t 11 mmHg), MAP (to 116 * 8 mmHg), and diastolic arterial pressure (DAP) (from 73 ? 12 mmHg to 94 t 10 mmHg) were noted during intubation in the thiopental sodium group. Hemodynamic parameters did not change during the 5-minute propofol loading infusion. However, BP decreased after the bolus administration of alfentanil (SAP decreased from 137 2 16 mmHg to 109 i 17 mmHg and MAP from 92 t 9 mmHg to 74 f 13 mmHg), returning to baseline during intubation and decreasing again 1 minute later. Nevertheless, BP in the total IV anesthesia group was never significantly different from that in the thiopental sodium group except during intubation, when BP as well as HR were higher in the thiopental sodium group. After the initial 20-minute study period, the BP profile was similar for both study groups, and hypotension (SAP <95 mmHg) was avoided in all patients. Figure 2 summarizes the recovery data. The times from awakening to correct orientation (7 2 5 minutes US 27 t 23 minutes) and to correct performance of the concentration test (12 t 12 minutes US 35 2 37 minutes) were shorter for patients anesthetized with the new technique. The absolute value of the SD was strikingly smaller for the total IV anesthesia group, indicating better predictability of early, more complete
recovery.
The
Effect of Anesthetic
time
to correct
technique
on
performance
the short-memory test did not differ (27 2 15 minutes for the propofol-alfentanil group UT37 2 17 minutes for the thiopental sodium group). No correlation was present between the duration of the propofol infusion (280 + 95 minutes) and the recovery test times. Blood concentrations of propofol for nine patients are shown in I;@NP 3. .l’he concentration reached 7.42 i 1.19 ygiml after the 5-minute loading infusion. After the first 30 minutes, the concentrations ranged from 3 ? 0.69 pgiml to 3.36 ? 1.17 kg/ml. The apparent steadystate concentration of propofol after the first 60 minutes of infusion was 3.14 t 0.78 kg/ml. The steadystate clearance (calculated as maintenance infusion/ mean blood concentration for time 60 minutes to the end of the infusion) was 2.254 f- 0.45 Limin. Patients woke up at 1.09 + 0.19 pgiml. FZgzlre 4 shows the variation in alfentanil plasma concentration. Since alfentanil administration was titrated to minimize the hemodynamic response to stimulation, a wide plasma concentration range was expected. The concentration varied between 128 ? 58 ng/ml and 252 ? 112 ngiml. At the moment of
Propofol blood
011 5
11
15 30
11
45
1
”
”
1
’
120 180 240 300STOP AWAKE infusion Time (minutes) 60
90
Figure 3. Blood concentration k SD.
Bo
lmean+S.D.i
Ior
of’
Behavior
concentration
of propofol.
Data are means
ALfentantlplasma concentration (mean+S.O.i
500
c
= E w
200-
2
100 0 0
Figure
2. Recovery
times for orientation, concentration, and short-memory tests. The times from the patients’ initial responses to commands to the correct performance of the tests are indicated. Data are means i SD. (N,O = nitrous oxide.)
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5
15
30 45 60 90 Time [minutes)
Figure 4. Plasma concentration tients. Data are means t- SD.
120 180 STOP AWAKE infusion
of alfentanil
for nine
pa-
extubation, ml.
the plasma concentration
was 79 2 34 ngl
Discussion Carlier et ~1.~~’ described a decrease in BP on induction of anesthesia with propofol. This decrease in BP can lead to a dangerous reduction in cerebral perfusion pressure, especially in patients with reduced cerebral compliance.“’ In the present study, a reduction in BP was avoided by using a loading infusion instead of a bolus dose. Only after the addition of alfentanil did BP decrease significantly. The addition of alfentanil to a propofol infusion can cause an important decrease in BP, even in the presence of a drug with vagolytic properties such as pancuronium. Careful drug titration and close monitoring of its effects are therefore recommended. However, a similar decrease in BP occurred after thiopental sodium and fentanyl administration. Since intracranial pressure was not measured in this study, no exact statements can be made about the cerebral perfusion pressure. Furthermore, every effort was made to maintain normocapnia during the induction period to avoid an increase in intracranial pressure caused by an increased arterial partial pressure of CO, (PCO,), which could provoke further impairment of cerebral perfusion pressure. When autoregulation is disturbed or its limits exceeded, endotracheal intubation can cause marked cardiocirculatory responses leading to deleterious increases in cerebral blood flow.“-‘” In patients with reduced intracranial compliance, such BP increases may reduce cerebral perfusion pressure and cause furthel- cerebral impairment. In the propofol-alfentanil treated patients, the cardiocirculatory response to intubation was limited to a return to baseline. However, in the thiopental sodium-fentanyl treated patients, a significant increase in HR and BP occurred, indicating that the stress response to intubation was not sufficiently blocked by the dose of fentanyl used. Because it was difficult to define comparable end points of anesthesia in the two treatment groups, recovery times were determined from the moment the patients first responded to simple commands to correct performance of the different recovery tests. All patients woke up from anesthesia within a reasonable time after the end of surgery (0 to 40 minutes), but the recovery times for orientation and concentration tests were significantly shorter for the propofolalfentanil treated patients, with a smaller SD. This situation allows for a more complete early neurologic evaluation. The concentration of propofol (3 t 0.69 kg/ml to
3.36 % 1.17 pgiml) is similar to the concentration previously described for total IV anesthesia for nonmajor abdominal surgery” and for computer-conThe calculated steady-state trolled anesthesia.“.‘” clearance (2.254 k 0.45 Limin) was greater than the steady-state clearance calculated from data resulting from short infusions by Shafer ct 01.” (1.96 i- 0.57 to 2.08 ‘r_ 0.70 Limin), Gepts et ul.” (I..5 to 1.9 Limin), and Schiittler et aLy5 (1.9 ? 0.1 Limin). Whether this finding is due to differences in patient population (u.g., patients in this study were treated with anticonvulsant medication) or to the small sample size cannot be determined. The mean propofol blood concentration at awakening (1.09 i 0.19 ~gimlj is similar to previously reported values. ’‘x’ The large variation in alfentanil plasma concentration is the result of the adjustments of lthe alfentanil administration to the differing analgesic demands of the individual patients. Ausems et (~1.‘~described the variation of alfentanil plasma concentration needed to block reaction to different stimulus inl:ensities. The alfentanil concentration at the moment of awakening in the present study (79 i: 34 ngiml) is well below the reported limit for spontaneous respiration (223 ng/ml with a 95% confidence limit: 197 to 249 ngiml).” The present authors found no correlation between the duration of propofol administration and the recovery test times. ‘I‘his finding may indicate that the duration of propofol administration, within the time limits studied, does not influence recovery time. Alternatively, it may be explained by the predominant influence of the large doses of’alfentanil on recovery times. Alfentanil has been found to increase cerebrospinal fluid pressure in patients with brain tumors.2K Others have not found any changes in cerebral blood flow or metabolism with doses up to 150 Fg/kg in humans.” Nevertheless, operative conditions were excellent in all of the present study patients. Finally, a total IV anesthetic technique with propofol and alfentanil allowed the present authors to avoid the administration of N,O. Its use in neuroanesthesia is controversial because it is a potent direct cerebral vasodilator.d-7 Furthermore, since it has been shown that N,O in the presence of brain ischemia in rats can worsen neuronal injury, one should consider not using it during surgery in the presence of human brain ischemia.“” The authors conclude that total IV anesthesia with the combined use of propofol and alfentanil provides a safe alternative to an anesthetic technique based on thiopental sodium, fentanyl, low-dose isoflurane, and X,0. The total IV technique results in safer circulatory conditions during intubation and earlier, more complete, and more predictable recovery. In addition, the use of N,O is avoided. J. Clin. Anesth., bol. 3, MarchiApl-il
1991
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Original
Contributions
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