Total Intravenous Anesthesia for Infants Tetralogy of Fallot: Sufentanil Versus Andreas
Barankay,
Correction Technique
of
MD, Josef A. Richter, MD, Richard Henze, MD, Peter Mitto, MD, and Paul Sptith, MD
The effects of two total intravenous anesthetic techniques were compared in 20 infants and children undergoing primary correction of tetralogy of Fallot (TOF). All patients (mean body weight, 11.4 f 4.2 kg; range, 6 to 20 kg; mean age, 32 f 21 months, range, 7 to 85 months) were premedicated with atropine, 0.02, mglkg, morphine, 0.2, mglkg, and flunitrazepam, 0.04 mg/ kg, intramuscularly, 1 hour preoperatively. Anesthesia was induced with 1 pg/ kg of sufentanil (S) and pancuronium, 0.1 mg/ kg, intravenously. Patients were ventilated with 100% oxygen. Hemodynamic parameters, heart rate (HR), systolic (SBP), diastolic (DBP) and mean arterial blood pressure (MAP), central venous pressure (CVP), and peripheral arterial blood oxygen saturation (SaO,) were recorded. Plasma concentrations of S, epinephrine (E), norepinephrine (NE), and blood gases were determined. To obtain a further depth of anesthesia, 10 patients (SM group) received 4 pg/ kg of S and 10 patients (SF group) received 4 pg/ kg of S in combination with flunitrazepam, 40 pg/ kg, in a randomized manner. Measurements were made before and after induction of anesthesia, before and after anesthetic
I
and Children Undergoing Sufentanil-Flunitrazepam
MPROVED RESULTS in correction of tetralogy of Fallot (TOF) have led to a modification of surgical strategy. Instead of a palliative procedure, symptomatic patients now undergo a corrective operation in early infancy, provided the pulmonary arteries are well developed. During surgery, the following changes may jeopardize hemodynamic stability and tissue oxygenation and should be prevented: decreases of pulmonary blood flow, systemic vascular resistance, or cardiac output.‘,* Proper premeditation as well as the careful selection of the anesthetic technique and drugs may minimize these risks. Although peripheral arterial oxygen saturation increases during anesthetic induction with inhalational or intravenous agents in patients with cyanotic congenital heart disease (CHD),‘~’ opioids seem to have some advantages in this patient group.h-8 With 100% oxygen or oxygen in air, both fentanyl (F) (25 to 75 kg/kg) and sufentanil (S) (5 to 20 kg/kg) have provided circulatory stability during induction in infants and children with CHD.9 However, complete suppression of responses to intense stimulation has not been achieved even with high-dose narcotics.‘“,” Therefore, the supplementation of F or S anesthesia with other agents, such as benzodiazepines or nitrous oxide, has been proposed to provide a reliable depth of anesthesia for the whole operative period. “A* However, the benefits of these systematically in combinations have not been investigated patients with CHD. The purpose of this prospective, randomized study was to compare the hemodynamic and catecholamine responses to intubation, surgical stimulation, and extracorporeal circulation (ECC) using S versus a S/flunitrazepam combination, in infants and children undergoing primary repair of TOF. This patient group was investigated because prevention of pulmonary and systemic hemodynamic changes and the suppression of stress responses is of paramount importance to maintain or improve their tissue oxygenation.
loading, 2 minutes after sternotomy, 15 minutes after initiation of extracorporeal circulation (ECC), and at sternal closure. Peak values for plasma S concentrations of 3.14 f 1.13 (SM group) and 3.45 f 97 ng/mL (SF group) were found before sternotomy. Following intubation HR. SBP, DBP, and MAP remained close to values measured before induction, but SaO, increased significantly (P < 0.01) in all patients. HR. SBP, and MAP decreased during anesthetic loading in both groups. Hemodynamics and plasma E and NE remained essentially unchanged after sternotomy in the SF group. In contrast, significant hemodynamic (SBP, MAP) and catecholamine (NE) responses were observed during this phase in the SM group. More patients (6 versus 2) needed adjuvant anesthetics in the SM group (P c 0.05). Thus S-flunitrazepam anesthesia compared with S alone ensured stable hemodynamics and was able to prevent elevations of plasma NE and E during surgical stimulation in infants and children with TOF. Copyright o 1992 by W.B. Saunders Company
MATERIALS
AND METHODS
After Institutional Review Board approval and parental consent, 20 infants and children, weighing 6 to 20 kg, were studied (Table 1). All patients received atropine, 0.01 mgikg, morphine, 0.2 mgikg, and flunitrazepam, 0.04 mgikg, intramuscularly, 60 minutes before anesthesia. Following the arrival of the patient in the operating room, a blood pressure cuff, electrocardiogram (ECG), and pulse oximeter were applied, and a peripheral vein was cannulated. Baseline data included heart rate (HR), systolic (SBP), diastolic (DBP), and mean (MAP) arterial blood pressure, peripheral arterial blood oxygen saturation (SaO,), and plasma catecholamines, epinephrine (E), and norepinephrine (NE). The patients were randomized to one of two groups: S monoanesthesia (SM) or Siflunitrazepam combination (SF). After preoxy genization via a face mask, anesthesia was induced with S, 1 pgikg, intravenously, and muscle relaxation was obtained with pancuronium, 0.1 mgikg, in both groups. Following intubation, all patients were ventilated with 100% oxygen via a nonrebreathing system keeping arterial carbon dioxide (PaCO,) tension between 30 to 40 mm Hg. Arterial and central venous catheters were placed percutaneously; thereafter, arterial pressure (SBP, DBP, MAP), central venous pressure (CVP), ECG, and end-tidal carbon dioxide tension (PeCO,) were continuously recorded. A loading dose of 4 ug/kg of S was given in the SM group and 4 kg/kg of S plus 40 pg/kg of flunitrazepam in the SF group in the 15minute period before surgery. Adjuvant medication (1 kg/kg of S or 40 kg/kg of flunitrazepam) was given to any patients who had increases in HR or SBP greater than 20% over preinduction levels. The frequency of this medication was recorded in both groups. Data acquisition included HR, SBP, DBP, MAP, CVP, SaO,, PeCO,, and arterial blood gases, as well as the plasma concentrations of E, NE, and S.
From the Institute for Anesthesiology, German Heari Center, Munich, Germany. Address reprint requests to J.A. Richter, MD, Institute for Anesthesiology, German Heart Center Munich, Lothstrasse 11, D-8000 Miinchen 2, Germany. Copyright o I992 by W.B. Saunders Company 1053-07701921060;?-0012$03.OOlO
Journalof Cardiothoracic and VascularAnesthesia, Vol6, No 2 (April), 1992: pp 185-189
185
186
BARANKAY ET Ai.
Table 1. Patient Characteristics
_
Group SM (n = 10) Age
35 ? 24
ho)
Group SF (n = 101 _._~_
(7-85)
22 i 17.5
.._._ ._
(7-59)
Body weight (kg)
11.8 ? 4.3
(7.1-20.5)
10.0 r 4.0
Height (cm)
90.2 -t 17.7
(69-l 23)
72.4 ? 25.6
(6.5-19) 166.108)
Body surface area (m’)
0.53 * 0.47
(0.36-0.90)
0.46 t- 0.12
(0.36-0.75)
255 i 55
(190-350)
Duration of Anesthesia (min)
232 I 27
(190.265)
ECC (min)
77 t 21
(55-l 15)
68% 17
(56-81)
Aortic crossclamping (min)
48&
(41-49)
42 -t 5
(37-45) (10.8-18.1)
11
Preoperative Hemoglobin (g/dL)
16.4 & 2.4
(13.5-20.1)
15.3 ? 2.3
Hematocrit (%)
51.0 + 9.6
(38-65)
47.0 t 6.9
Preoperative p-blocker therapy incidence
2110
(37-58) 3110
NOTE. Mean + SD, range.
Hemodynamic changes arc shown in Fig 1. HR decreased during loading in both groups. Following sternotomy HR remained constant in the SF group, and its increase in the SM group was nonsignificant. There were significant differences found in SBP and MAP in the two groups before ECC. After loading, SBP decreased in both groups. Following sternotomy, it remained stable in the SF group, but rose significantly in the SM group. After extracorporeal circulation, SBP in the SM group was above and in the SF group below levels measured before loading. Alterations in MAP were similar to those of SBP in both groups. DBP decreased slightly during loading in both groups. Changes measured following sternotomy were not significant. No significant changes in CVP occurred. The course of plasma E in the SF group is shown in Fig 2. Deepening of anesthesia led to a decrease of plasma E concentrations. This is also true for the only patient with a high initial level. Plasma E values remained essentially unchanged during sternotomy. After the expected increase during ECC, E values almost returned to levels measured before loading. In the SM group (Fig 3), plasma E decreased as well until sternotomy. As a response to sternotomy, there was a marked increase found in 2 of 10 patients. At sternal closure, plasma E values remained high ( > 250 pg/mL) in 4 cases. Plasma catecholamines are listed in Table 3. Although mean values for plasma E were markedly higher in the SM group after sternotomy, during ECC, and at sternal closure, the large variability among patients prevented the results from achieving statistical significance. There was a significant increase in plasma NE levels found
These were measured after intubation, before and after anesthetic loading, 2 minutes after sternotomy, 15 minutes after initiation of ECC, and at sternal closure. Plasma concentrations of E and NE were measured with high-pressure liquid chromatography (HPLCEC). The interassay variability for NE was 3.9%, and for E 5.8%. The intraassay variabilities for these assays were 4.0% (NE) and 4.3% (E). For measurement of plasma S concentration, the radioimmunoassay (RIA) method was used. The amount of blood taken for laboratory tests was replaced with 6% hydroxyethyl starch before ECC. A standardized ECC technique was used. The prime consisted of 500 mL of blood, 3 mL/kg of mannitol20%, and 2.5 mL/kg of sodium bicarbonate 4.2%. Analysis of variance (ANOVA) was used to compare the SM group with the SF group with regard to hemodynamics and plasma catecholamines. To compare changes within groups, the Wilcoxon signed-rank test was applied. The proportion of patients requiring adjuvant medication was compared using a x2. Statistical significance was defined for values with P < 0.05. RESULTS
in the demographic difference data between the patients in the two groups (Table 1). Preoperative hemoglobin and hematocrit values, incidence of p-blocker therapy, and duration of anesthesia and ECC were comparable. Following anesthetic induction and intubation, HR, SBP, DBP, and MAP remained close to values measured before induction in both groups (Table 2). Induction of anesthesia resulted in a marked increase in SaO, (P < 0.01) in all patients. However, arterial oxygen desaturation was still present (SM group: 86.5 -t 11.5%; SF group: 88.6 2 7.6%). SaO, correlated well with oxygen saturation, measured by blood gas analysis (r = 0.88, P = 0.001). There
was
no statistical
Table 2. Hemodynamics and SaO, During Anesthetic Induction Group SM (n = 10) Pre
Induction HR (beats/min)
122 2 27
SBP (mm Hg)
106?
15
DBP (mm Hg)
60+
10
SaO, (%)
77+- 13
‘P < 0.01 compared with preinduction data.
Group SF (n = 10) Post
PW
Induction 118 + 15 98+
16
Post
Induction
Induction
131 2 26
134 + 17
101 2 18
100 + 19
58 r 14
60r
85 + IO*
82 + 6
IO
622
11
86 ? 8*
SUFENTANIL vs SUFENTANIL-FLUNITRAZEPAM
IN TOF
2000 1600 1600
--o -
1400
SM SF
1200 1000 600
I
0 0 n 0 + x 0 I A -
Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7 6 9 10
i
i
J
600
i
400
4---Jbefore after after loading s;i;rn-
200 0
40beioreatierafiercsternal loading stemoclosure
ECC sternal closure
in the SM group, but not in the SF group following sternotomy. Plasma S concentrations (Fig 4) reached their peak levels of 3.14 2 1.13 ng/mL in the SM group and 3.45 + 97 ng/mL in the SF group before sternotomy. In spite of comparable plasma S concentrations, the need for adjuvant medication (1 kg/kg of S or 40 pg/kg of flunitrazepam) to ensure adequate anesthesia after ECC was considerably higher (P < 0.05) in the SM group (6 patients) compared with the SF group (2 patients). No patients required positive inotropic stimulation; one patient in each group received dopamine, 3 pg/kg, to ensure adequate urinary output after ECC. All patients survived the operation and were discharged from the hospital. DISCUSSION
In patients with TOF, in whom hemodynamic changes caused by anesthetic drugs and/or management might
1600
Ilg/mL
i
1600 1400 1200 1000 600
??
0 a 0 + x 0 9 A *
Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7 8 9 10
600 400
L
200 0
1
=e
_ before after induction
before
after loading
after
before loading
after sternotomy
ECC
sternal closure
tomy
Fig 1. Hemodynamic changes during anesthesia (mean f SEM). Abbreviations: SM. sufentanil monoanesthesia group; SF, sufentanilflunitrazepam group; HR, heart rate; CVP, central venous pressure; SBP, systofii blood pressure; DBP, diastolic blood pressure; ECC, extracorporeal circulation.
2000
before after induction
after sternotomy
ECC
sternal ClOSW2
Fig 2. Epinephrine plasma concentrations in the SF group (Patient No. 6 arrived apparently not well sedated in operating room). Abbreviations: SF group, sufentanil-flunitrazepam anesthesia; ECC, extracorporeal circulation; Pat, patient.
Fig 3. Epinephrine plasma concentrations in the SM group. (Patient no. 7 showed also marked increases in HR and blood pressure after stemotomy. Patients no. 2,6, and 9 needed adjuvant medication after ECC.)
induce marked deterioration of tissue oxygenation, the effects of two total intravenous anesthetic techniques were compared. Only infants and children with a body weight of more than 6 kg were selected, because the pharmacokinetits of S are different in smaller infants in terms of the volume distribution of sufentani1.‘3,‘4 The efficacy, safety, and hemodynamic response to SM has been previously evaluated in infants and children with CHD,%“.L3 In these studies, different S doses (5 to 20 kg/kg) were used and given either as a single bolus for induction and maintenance of anesthesia, or as a short infusion following anesthetic induction and intubation. In most reports, S provided marked hemodynamic stability during induction and decreased pulmonary vascular resistance, thereby increasing pulmonary blood flow and systemic oxygenation in children with CHD. In this respect, the effects of S and F, given in high doses, were comparable.’ However, the use of S as a sole anesthetic in bolus form did not provide a reliable depth of anesthesia for suppression of cardiovascular responses to noxious stimuli.” With respect to this point, the efficacy of high doses of S, 15 to 2.5 kg/kg, was also unable to be verified. Consequently, the use of additional anesthetic agents was suggested.l’.‘* A previous study by this group demonstrated that S in combination with nitrous oxide/oxygen (1:l) ensured stable hemodynamits during all phas,es of anesthesia before ECC and is also sufficient to prevent elevation of plasma catecholamines during surgical stimulation in a group of infants and children with CHD.6 In this study, in which a cumulative dose of 4 pg/kg of S was used, mean plasma concentrations of 1.92 ? 0.73 ng/‘mL of S were found at surgical stimulation. Patient groups in all the studies previously mentioned were not homogenous, including various types of cyanotic and noncyanotic heart malformations. In most of these studies, measurements were limited to a particular phase during the operation. In the present study, the data collected demonstrated the advantage of the combined use of opioids with a benzodiazepine over narcotic analgesics as the sole anesthetic agent
188
Table 3. Plasma Catecholamines Eplnephrine
(pg/mL)
SM
Norepinephrlne SF
Group
SM
Group
(pqr mL) SF
Group
Group
Preinduction
37 k 41
95 f 143
255 ?r 179
262 % 69
Postintubation
71 k 102
43 k 75
194 + 119
183 ? 88
Preloading
63 t 122
62 t 135
115 +_83
183 i 151
Postloading
46 k 96
9+
11
84 f 81
57 f 60
194 ? 255*
94 ?I 66
Poststernotomy
368 + 936
12 k 10
ECC (15 min)
418 + 544
163 ? 211
292 t 107
217 t 182
Sternal closure
585 5 490
96 t- 108
520 k 218
292 t 201
*P < 0.05 after sternotomy versus after loading
in terms of hemodynamic profiles and catecholamine responses during the operative period. The technique of drug administration corresponded to the authors’ routine clinical practice. A potent premeditation was given and an induction dose of S was followed by a loading dose. Using this method of a cumulative dose of 5 pg/kg of S, the highest S plasma concentrations (> 3 ng/mL) were measured in both groups after anesthetic loading. At this time, as an effect of deepening of anesthesia, the lowest HR and blood pressure values were found in both groups. In spite of comparable S plasma concentrations and hemodynamic parameters, intergroup differences were found with regard to hemodynamic and catecholamine responses to surgical stimulation. There was marked hemodynamic stability in the SF group, but significant increases in blood pressure and plasma NE in the SM group. These differences can be explained by the combined application of flunitrazepam and S. In addition to its anxiolytic and sedative/hypnotic properties, flunitrazepam is known to enhance the effects of
5 -
nglml
TT
4-
3-
2-
l-
before after induction
before after loading
after ECC sternotomy
sternal closure
Fig 4. S plasma concentrations (mean f SEM). Abbreviations: SM group, sufentanil monoanesthesia; SF group, sufentanil-flunitrazepam anesthesia; ECC, extracorporeal circulation.
narcotic analgesics.” Clinical studies in adult cardiac pa tients have shown that the dose of F needed for anesthetic induction can be markedly reduced by the additional use of flunitrazepam.” The advantages of a combined anesthetic technique in children with acyanotic heart lesions have been demonstrated by Morgan et al.’ The patients given a total dose of 75 kg/kg of F and 0.4 mg/kg of diazepam showed no change from baseline in HR, blood pressure, or catecholamine levels until ECC. The hemodynamic stability was superior to that reported with 50 to 7.5 pg/kg of F alone. F monoanesthesia (30 kg/kg) followed by an infusion of 0.3 pg/kg/min was compared with the combined application of 30 pg/kg of F and 50% nitrous oxide by Crean et al’” in children with a range of CHD, including cyanotic CHD, such as TOF or transposition of the great arteries. In their study, in which the loading dose of F was intentionally kept smaller than dose schedules used in adults, F plasma concentrations were about 34 ng/mL at the time of sternotomy. No elevation in blood pressure was registered as a response to surgical stimulation if F was combined with nitrous oxide. They suggested the use of a combination of F with a more suitable anesthetic agent because nitrous oxide might negatively affect the consequences of possible air embolization following ECC. The application of a benzodiazepine has a further advantage in that the USC of 100% oxygen leads to improved tissue oxygenation in infants and children with cyanotic CHD. This study suggests that in combination with 40 pg/kg of flunitrazepam no more than 5 pg/kg of S is needed to ensure adequate anesthesia for the whole operative period. However, more than 50% of the patients require adjuvant anesthetic medication, if S is not combined with flunitrazepam. Both intravenous techniques are suitable for infants and children undergoing primary elective correction of TOF. However, in contrast to the SF technique, increases in blood pressure and plasma catecholamines during surgical stimulation were observed in the SM groups.
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SUFENTANIL
vs SUFENTANIL-FLUNITRAZEPAM
189
IN TOF
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