Total Intravenous Anesthesia: Effects of Opioid Versus Hypnotic Supplementation on Autonomic Responses and Recovery Terri G. Monk,
MD,
Yifeng Ding,
MD,
and Paul F. White,
PhD, MD, FFARACS
Division of Clinical Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, and Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas
During radical prostatectomy procedures under total intravenous anesthesia, acute hemodynamic responses to retropubic dissection (30% 8%to 36% & 12% [mean SD]increases in mean arterial pressure) were treated with supplemental doses of either an opioid analgesic (alfentanil) or a sedative-hypnotic (p.ropofo1) to return the mean arterial pressure to within 10% of the preincision value. Although both drugs were effective, control with propofol required 10.1 2 2.5 min compared with 6.3 ? 2.6 min in the alfentanil group (mean SD; P < 0.01). Plasma stress hormone concentrations increased significantly in response to this surgical stimulus: epinephrine increased from 246% 169% to 283% 5 330%; norepinephrine increased from 44% 33% to 83% 104%; and antidiuretic hormone increased from 1300% & 1591% to 1700% 1328%. Both alfentanil and propofol were equally effective in returning
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*
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T
otal intravenous anesthesia (TIVA) involves the combined use of intravenous sedative-hypnotic, opioid analgesic, and muscle-relaxant drugs (14).Alfentanil and propofol are rapid, shortacting compounds with similar pharmacokinetic profiles. Although pharmacokinetic modeling suggests that sufentanil is an acceptable opioid analgesic to combine with propofol infusions during TIVA techniques lasting 130% of ideal body weight), clinically significant hepatic or renal dysfunction, endocrine disease, and inadequately controlled chronic hypertension. On arrival in the preoperative holding area, a peripheral venous catheter was inserted, and all patients received midazolam (2-4 mg IV).After placement of a radial artery catheter, patients were transported to the operating room, and preinduction (baseline) hemodynamic values were obtained. Anesthesia was induced with alfentanil (20 pgkg), propofol (1.5 mgkg IV), and vemonium (0.1 mgkg IV).After tracheal intubation, anesthesia was maintained with constant-rate infusions of alfentanil (0.5 pg.kg-'-min-') and propofol (50 pg.kg-'.min-'). Neuromuscular blockade was maintained with a vecuronium infusion at 0.8 pg.kg-'.min-'. Ventilation was controlled with 30% oxygen in air to maintain an end-tidal carbon dioxide tension (PETCO~) of 34 k 3 mm Hg (mean k SD). Arterial blood samples were obtained 1-2 min before skin incision to determine Paco, (37 2 5 mm Hg). The MAP and HR were continuously monitored using an integrated monitor (Cardiocap11, Datex Medical Instrumentation, Tewksbury, Mass.). Central venous pressure was monitored via a catheter placed in an internal jugular vein after tracheal intubation. The central venous pressure was maintained between 3 and 8 mm Hg throughout the study period by administering crystalloid and hetastarch (Hespan) or blood products. Blood samples were obtained from the arterial catheter for determination of plasma catecholamines, vasopressin (antidiuretic hormone [ADH]), @endorphin, cortisol, insulin, pancreatic polypeptide, and C-peptide concentrations at 1-2 min before skin inci-
MONK ET AL. TIVA WITH ALFENTANIL AND PROPOFOL
799
sion (preincision) and 3-5 min after the onset of the hypertensive response during retropubic dissection (pretherapy). Plasma alfentanil and propofol concentrations were measured using arterial blood samples obtained at the same time intervals. Blood for catecholamine analysis was collected into tubes containing reduced glutathione and ethyleneglycol bis(aminoethylether)tetraacetate, and the blood samples for the remainder of the hormone assays were collected into ethylenediaminetetraacetate-containing tubes. These samples were immediately placed on ice and the plasma separated with a refrigerated centrifuge. All samples were stored at -70°C until the assays were performed. Epinephrine and norepinephrine concentrations were determined using radioenzymatic assay techniques, with minimal assay sensitivities of 20 pg/mL and coefficients of variation of +lo%; all other hormone concentrations were determined using radioimmune assay techniques (14-17). The lower limits of sensitivity for the radioimmune assay were ADH (1 pg/mL), Mndorphin (8 pg/mL), cortisol (1 pg/dL), insulin (4 pU/mL), pancreatic polypeptide (20 pg/mL), and C-peptide (0.05 ng/mL). Plasma alfentanil concentrations were measured using a standardized radioimmunoassay with a lower limit of sensitivity of 5 ng/mL (18), and plasma propofol concentrations were measured using high-performance liquid chromatography by ICI Americas Inc. (Wilmington, Del.), with a lower limit of sensitivity of 50 ng/mL. Patients exhibiting an increase in MAP of 25% or more above their preincision MAP for a minimum of 3 min were randomly treated using supplemental alfentanil or propofol to return the MAP to within 10% of the preincision value. In the alfentanil group, patients initially received a lO-@kg bolus dose, and the infusion rate was increased by 0.5 pg-kg-'-min-' (with an additional bolus dose and increases in the infusion rate repeated every 2-3 min until the MAP decreased). In the propofol group, patients initially received a 0.3-mgkg bolus dose, and the.infusion rate was increased by 50 pg-kg-'.min-' (these supplemental dosages were repeated every 2-3 min until the MAP decreased). After maintaining a stable MAP for 10 min, repeat blood samples were obtained for determination of posttherapy hormone as well as analgesic and hypnotic drug concentrations. This sampling point was chosen because plasma catecholamines have a plasma half-life of 5 min. On initiating skin closure, the vecuronium and alfentanil infusions were discontinued. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine (0.07 mg/kg) and glycopyrrolate (0.01 mg/kg), and the propofol infusion was discontinued. The times from termination of the propofol infusion to spontaneous eye opening, purposeful response to verbal commands, adequate spontaneous ventilation, tracheal extubation, and orientation (to person, place, and time) were recorded. The recovery endpoints were evaluated at 5-10-s intervals after spontaneous eye opening. If adequate spontaneous ventilation did not occur within 10 min 2 4 5 mm Hg), naloxone (0.04 mg IV) (with PETCO~ was administered every 60 s until spontaneous ventilation was adequate (PETCO~ 5 min after achieving adequate pain control, labetalol ( 5 1 0 mg IV) or hydralazine (2.5-5 mg IV) was administered as needed to return the MAP value to within 10% of the preoperative baseline value. The dosage requirements for analgesic, antiemetic, and antihypertensive drugs in the PACU were recorded. Standardized PACU discharge criteria required that the patient be alert and oriented, have a stable MAP, HR, and respiratory rate, hemoglobin oxygen saturation >%YO, and that residual side effects (e.g., nausea, pain) be minimal. At the time of discharge from the PACU, patients were given a patient-controlled analgesia device (Baxter Infusor, Chicago, Ill.) that allowed them to selfadminister morphine sulfate (2 mg [0.5 mL] IV) at minimal intervals of 6 min. All patients were visited daily to evaluate their overall recovery status and analgesia usage. On the fifth postoperative day, the
Table 1. Demographic Characteristics, Baseline Hemodynamic Values, and Plasma Drug Concentrations in the Two Treatment Groups Alfentanil ( n = 11) Age (Yr) Weight (kg) Height (cm) Preexisting conditions Chronic hypertension Coronary artery disease PBlocker therapy Ca+-channel blocker therapy Mean arterial blood pressure (mm Hg) Heart rate (beats/&) Alfentanil concentration (ng/mL) Preincision Pretherapy Propofol concentration (pg/mL) Preincision Pretherapy Surgical time (min) Values are mean
? SD,
*
Propofol (n = 11) ~
66 6 83 f 11 177 f 9 3 L
2
67 f 6 83 +- 9 175 f 5
4 3 3 2
2 105 f 10 70 f 9
100 f 11 67 f 11
64 f 15 67 f 19
79 +- 16 80 f 14
1.7 f 1.0 1.5 2 0.6 245 f 22
1.9 f 0.6 2.2 & 1.9 225 & 64
or numbers
patients completed a questionnaire with regard to their satisfaction with the anesthetic technique. Data were analyzed using the STATA statistical analysis program, with one-way analysis of variance for continuous variables and the $ test for discrete variables. Changes over time were evaluated using repeated measures of analysis of variance and Student’s t-test, with a Bonferroni correction for multiple comparisons. Intergroup differences were evaluated using Tukey’s post hoc test. Differences were considered to be statistically significant if the P value was
MD,
Yifeng Ding,
MD,
and Paul F. White,
PhD, MD, FFARACS
Division of Clinical Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, and Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas
During radical prostatectomy procedures under total intravenous anesthesia, acute hemodynamic responses to retropubic dissection (30% 8%to 36% & 12% [mean SD]increases in mean arterial pressure) were treated with supplemental doses of either an opioid analgesic (alfentanil) or a sedative-hypnotic (p.ropofo1) to return the mean arterial pressure to within 10% of the preincision value. Although both drugs were effective, control with propofol required 10.1 2 2.5 min compared with 6.3 ? 2.6 min in the alfentanil group (mean SD; P < 0.01). Plasma stress hormone concentrations increased significantly in response to this surgical stimulus: epinephrine increased from 246% 169% to 283% 5 330%; norepinephrine increased from 44% 33% to 83% 104%; and antidiuretic hormone increased from 1300% & 1591% to 1700% 1328%. Both alfentanil and propofol were equally effective in returning
*
*
*
*
*
*
*
T
otal intravenous anesthesia (TIVA) involves the combined use of intravenous sedative-hypnotic, opioid analgesic, and muscle-relaxant drugs (14).Alfentanil and propofol are rapid, shortacting compounds with similar pharmacokinetic profiles. Although pharmacokinetic modeling suggests that sufentanil is an acceptable opioid analgesic to combine with propofol infusions during TIVA techniques lasting 130% of ideal body weight), clinically significant hepatic or renal dysfunction, endocrine disease, and inadequately controlled chronic hypertension. On arrival in the preoperative holding area, a peripheral venous catheter was inserted, and all patients received midazolam (2-4 mg IV).After placement of a radial artery catheter, patients were transported to the operating room, and preinduction (baseline) hemodynamic values were obtained. Anesthesia was induced with alfentanil (20 pgkg), propofol (1.5 mgkg IV), and vemonium (0.1 mgkg IV).After tracheal intubation, anesthesia was maintained with constant-rate infusions of alfentanil (0.5 pg.kg-'-min-') and propofol (50 pg.kg-'.min-'). Neuromuscular blockade was maintained with a vecuronium infusion at 0.8 pg.kg-'.min-'. Ventilation was controlled with 30% oxygen in air to maintain an end-tidal carbon dioxide tension (PETCO~) of 34 k 3 mm Hg (mean k SD). Arterial blood samples were obtained 1-2 min before skin incision to determine Paco, (37 2 5 mm Hg). The MAP and HR were continuously monitored using an integrated monitor (Cardiocap11, Datex Medical Instrumentation, Tewksbury, Mass.). Central venous pressure was monitored via a catheter placed in an internal jugular vein after tracheal intubation. The central venous pressure was maintained between 3 and 8 mm Hg throughout the study period by administering crystalloid and hetastarch (Hespan) or blood products. Blood samples were obtained from the arterial catheter for determination of plasma catecholamines, vasopressin (antidiuretic hormone [ADH]), @endorphin, cortisol, insulin, pancreatic polypeptide, and C-peptide concentrations at 1-2 min before skin inci-
MONK ET AL. TIVA WITH ALFENTANIL AND PROPOFOL
799
sion (preincision) and 3-5 min after the onset of the hypertensive response during retropubic dissection (pretherapy). Plasma alfentanil and propofol concentrations were measured using arterial blood samples obtained at the same time intervals. Blood for catecholamine analysis was collected into tubes containing reduced glutathione and ethyleneglycol bis(aminoethylether)tetraacetate, and the blood samples for the remainder of the hormone assays were collected into ethylenediaminetetraacetate-containing tubes. These samples were immediately placed on ice and the plasma separated with a refrigerated centrifuge. All samples were stored at -70°C until the assays were performed. Epinephrine and norepinephrine concentrations were determined using radioenzymatic assay techniques, with minimal assay sensitivities of 20 pg/mL and coefficients of variation of +lo%; all other hormone concentrations were determined using radioimmune assay techniques (14-17). The lower limits of sensitivity for the radioimmune assay were ADH (1 pg/mL), Mndorphin (8 pg/mL), cortisol (1 pg/dL), insulin (4 pU/mL), pancreatic polypeptide (20 pg/mL), and C-peptide (0.05 ng/mL). Plasma alfentanil concentrations were measured using a standardized radioimmunoassay with a lower limit of sensitivity of 5 ng/mL (18), and plasma propofol concentrations were measured using high-performance liquid chromatography by ICI Americas Inc. (Wilmington, Del.), with a lower limit of sensitivity of 50 ng/mL. Patients exhibiting an increase in MAP of 25% or more above their preincision MAP for a minimum of 3 min were randomly treated using supplemental alfentanil or propofol to return the MAP to within 10% of the preincision value. In the alfentanil group, patients initially received a lO-@kg bolus dose, and the infusion rate was increased by 0.5 pg-kg-'-min-' (with an additional bolus dose and increases in the infusion rate repeated every 2-3 min until the MAP decreased). In the propofol group, patients initially received a 0.3-mgkg bolus dose, and the.infusion rate was increased by 50 pg-kg-'.min-' (these supplemental dosages were repeated every 2-3 min until the MAP decreased). After maintaining a stable MAP for 10 min, repeat blood samples were obtained for determination of posttherapy hormone as well as analgesic and hypnotic drug concentrations. This sampling point was chosen because plasma catecholamines have a plasma half-life of 5 min. On initiating skin closure, the vecuronium and alfentanil infusions were discontinued. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine (0.07 mg/kg) and glycopyrrolate (0.01 mg/kg), and the propofol infusion was discontinued. The times from termination of the propofol infusion to spontaneous eye opening, purposeful response to verbal commands, adequate spontaneous ventilation, tracheal extubation, and orientation (to person, place, and time) were recorded. The recovery endpoints were evaluated at 5-10-s intervals after spontaneous eye opening. If adequate spontaneous ventilation did not occur within 10 min 2 4 5 mm Hg), naloxone (0.04 mg IV) (with PETCO~ was administered every 60 s until spontaneous ventilation was adequate (PETCO~ 5 min after achieving adequate pain control, labetalol ( 5 1 0 mg IV) or hydralazine (2.5-5 mg IV) was administered as needed to return the MAP value to within 10% of the preoperative baseline value. The dosage requirements for analgesic, antiemetic, and antihypertensive drugs in the PACU were recorded. Standardized PACU discharge criteria required that the patient be alert and oriented, have a stable MAP, HR, and respiratory rate, hemoglobin oxygen saturation >%YO, and that residual side effects (e.g., nausea, pain) be minimal. At the time of discharge from the PACU, patients were given a patient-controlled analgesia device (Baxter Infusor, Chicago, Ill.) that allowed them to selfadminister morphine sulfate (2 mg [0.5 mL] IV) at minimal intervals of 6 min. All patients were visited daily to evaluate their overall recovery status and analgesia usage. On the fifth postoperative day, the
Table 1. Demographic Characteristics, Baseline Hemodynamic Values, and Plasma Drug Concentrations in the Two Treatment Groups Alfentanil ( n = 11) Age (Yr) Weight (kg) Height (cm) Preexisting conditions Chronic hypertension Coronary artery disease PBlocker therapy Ca+-channel blocker therapy Mean arterial blood pressure (mm Hg) Heart rate (beats/&) Alfentanil concentration (ng/mL) Preincision Pretherapy Propofol concentration (pg/mL) Preincision Pretherapy Surgical time (min) Values are mean
? SD,
*
Propofol (n = 11) ~
66 6 83 f 11 177 f 9 3 L
2
67 f 6 83 +- 9 175 f 5
4 3 3 2
2 105 f 10 70 f 9
100 f 11 67 f 11
64 f 15 67 f 19
79 +- 16 80 f 14
1.7 f 1.0 1.5 2 0.6 245 f 22
1.9 f 0.6 2.2 & 1.9 225 & 64
or numbers
patients completed a questionnaire with regard to their satisfaction with the anesthetic technique. Data were analyzed using the STATA statistical analysis program, with one-way analysis of variance for continuous variables and the $ test for discrete variables. Changes over time were evaluated using repeated measures of analysis of variance and Student’s t-test, with a Bonferroni correction for multiple comparisons. Intergroup differences were evaluated using Tukey’s post hoc test. Differences were considered to be statistically significant if the P value was
