A clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--2. Pharmacokinetics following the end of continuous ketamine infusion

Ten surgical patients who received various operative procedures including abdominal surgery and ENT surgery were the subjects of the pharmacokinetic study of total intravenous anesthesia with droperidol, fentanyl and ketamine. Six arterial samples were taken through an indwelling catheter in the left radial artery to measure plasma levels of ketamine and its metabolites by means of gas liquid chromatography. Two hours following the end of the ketamine infusion, plasma ketamine levels decreased to 14% of the control value (0.81 micrograms.ml-1), while metabolite I (K1) was still about 1.8 micrograms.ml-1 in the plasma. The control value of plasma ketamine just before the end of its infusion had not any significant relationship with the total dose of ketamine, total dose of fentanyl, blood loss or fluid given. The results of our study suggest that long continuous ketamine infusion would be safe as judged by its pharmacokinetics.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--1. Introduction

We have developed a new method of total intravenous anesthesia with droperidol, fentanyl and ketamine and have administered it to more than 400 surgical patients, ranging in ages from 4 to 80 years. Cardiac and neurosurgical patients were excluded. After establishing a routine monitoring, droperidol 0.06-0.1 ml.kg-1 was slowly given. After 5 minutes, fentanyl 1-2 micrograms.kg-1 and ketamine 1.0-1.5 mg.kg-1 were slowly administered intravenously. Trachea was intubated following intravenous succinylcholine. A total dose of 5-15 micrograms.kg-1 of fentanyl was given intravenously with a continuous infusion of ketamine 2 mg.kg-1.hr-1 during surgical procedure. Air and O2 (FIO2 0.30-0.35) were given and muscle relaxation was achieved with necessary dose of intravenous pancuronium or vecuronium and no inhaled anesthetic was given. Total intravenous anesthesia has many advantages such as no air pollution in the operating theatre, empty bowels, no organ (hepato-renal) toxicity, good peripheral perfusion and low cost, while this method has several disadvantages to overcome such as hypertension. There are many anesthetic agents for total intravenous anesthesia. However, sufentanil, alfentanil and propofol are not available. Droperidol, fentanyl and ketamine are the best combination for this purpose in Japan so far.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--15. Application for cardiac anesthesia]

Total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK) was administered to 36 cardiac patients who underwent mostly coronary artery bypass graft or heart valve replacement. The induction and maintenance of anesthesia using this technique were almost satisfactory with little decrease in systolic blood pressure (SBP), although six patients among the early 21 patients developed hypotension below 90 mmHg (SBP) during the induction, and required vasopressors. Half of the patients had hypertensive episode of above 180 mmHg (SBP), from the start of operation to onset of cardiopulmonary bypass, which was safely and effectively overcome by a small dose of antihypertensive agents. Total intravenous anesthesia with DFK was accompanied with much more hypertensive episodes compared to anesthesia with moderate dose fentanyl (30 micrograms.kg-1) combined with enflurane. However, the incidence of cardiovascular complications following anesthesia was not statistically different between the two anesthesia groups. In addition, most of the patients with DFK showed a rapid awaking time with relatively good postoperative cardiovascular stability. These findings suggest that total intravenous anesthesia with DFK is accompanied with minimal hemodynamic changes during and after open heart surgery.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl, and ketamine--6. Effects on postoperative liver function

We have developed a new method of total intravenous anesthesia with droperidol, fentanyl, and ketamine, and have administered it to more than 700 surgical patients. We studied whether this method of anesthesia would influence postoperative liver function or not. A total of sixty elective surgical patients were the subjects of this study. Thirty patients underwent total hysterectomy under either the total intravenous anesthesia (15 patients) or modified neurolept-anesthesia with pentazocine (15 patients). The remaining 30 patients underwent gastrectomy under either this total intravenous anesthesia (15 patients) or enflurane-N2O anesthesia (15 patients). The hepatic function was evaluated as judged by s-GOT, s-GPT, ALP, gamma-GPT and total bilirubin levels, before anesthesia and during the first to third postoperative day. The patients for gastrectomy under enflurane-N2O anesthesia had significantly increased postoperative gamma-GPT levels compared with the patients of total intravenous anesthesia. Any other variables showed no significant difference among groups. We consider that this method of total intravenous anesthesia has no adverse effects on postoperative liver function as compared with other usual anesthetic methods.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--11. Effect on epidural pressure]

We have developed a new method of total intravenous anesthesia using ketamine, fentanyl and droperidol (NLA-FK). There are many reports describing a significant increase in cerebrospinal fluid pressure (CSFP) during ketamine administration, but little is known about changes in CSFP during NLA-FK. As epidural pressure (EP) is considered as a good index for CSFP, we measured it in 12 patients under either NLA-FK or isoflurane anesthesia, who underwent gastrectomy. In the NLA-FK group the EP increased significantly by 26% at the induction of anesthesia as compared with the preinduction level, and it decreased to the preinduction level 30 minutes after the induction. Thereafter the pressure was not appreciably changed. In the isoflurane group EP significantly decreased by 16% at induction, but the pressure significantly increased by 29% 30 minutes after the induction as compared with the preinduction level. The change was similar to that of the NLA-FK group. Although the increase in the EP during the induction of NLA-FK is significant, it is considered to be within normal ranges. However, further detailed clinical study is needed to attenuate the significant increase in the EP during the induction of NLA-FK.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--13. Application for pediatric patients]

Total intravenous anesthesia with droperidol, fentanyl, and ketamine (FK) was administered to 56 pediatric surgical patients ranging in ages from 5 to 15 years to evaluate their hemodynamics during anesthesia, post-operative hepatic as well as renal functions, and post-operative sedation as well as analgesia. These data were compared with those of the patients who underwent almost the same surgical procedures under enflurane-N2O anesthesia. The post-operative s-GOT, s-GPT, BUN, creatinine levels were not elevated significantly as compared with pre-operative levels in the FK group. As compared with those patients who received enflurane anesthesia, the blood pressure in the FK groups was higher by 15-30 mmHg, but it was stable during anesthesia without any complications. Their post-operative sedation and analgesia were better in the FK group than in the enflurane group and the complications such as nausea and vomiting were observed less frequently in the FK patients than in the patients who received anesthesia with ketamine alone reported in literatures. The data described above suggest that this method of anesthesia deserves further detailed clinical trials for pediatric patients.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--9. Control of intraoperative hypertension with diltiazem

Intraoperative hypertension over 160 mmHg systolic and sinus tachycardia over 100 bpm are often observed during total intravenous anesthesia with droperidol, fentanyl and ketamine. Fifty-seven surgical patients who developed hypertension over 160 mmHg systolic during various operative procedures under this type of anesthesia were given diltiazem intravenously to overcome the situation. Their blood pressure and heart rate decreased soon after the administration of diltiazem. The rate pressure product was reduced significantly. Neither preoperative hypertension nor difference of doses between 5 mg and 10 mg of diltiazem had any significant relationship with hypotensive effect of intravenous diltiazem. But the higher the systolic-pressure was just before the administration of diltiazem, the more effective diltiazem was. No adverse effects with this drug was observed. We can conclude that intravenous diltiazem in a dose of 5 mg or 10 mg may be repeatedly given to overcome hypertension or sinus tachycardia during this type of anesthesia without any adverse effects.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--7. Effects on natural killer cell activity

Twenty four patients who underwent ophthalmic surgery were studied to evaluate activities of natural killer (NK) cells during and following total intravenous anesthesia with droperidol, fentanyl and ketamine. They were divided into three equal groups according to anesthetic methods employed. In enflurane group, anesthesia was induced with thiopental 5 mg.kg-1 and succinylcholine 1 mg.kg-1, and maintained with 1-2% enflurane, nitrous oxide (50%) and oxygen (50%). In original NLA group, anesthesia was induced as above and maintained with droperidol 0.15 mg.kg-1, fentanyl 5-10 micrograms.kg-1, nitrous oxide (70%) and oxygen (30%). The patients of total intravenous anesthesia group received droperidol 0.15 mg.kg-1, ketamine 2 mg.kg-1 and succinyl-choline 1 mg.kg-1 for induction of anesthesia, and then were given fentanyl 5-15 micrograms.kg-1, ketamine 2 mg.kg-1.hr-1 and oxygen (30%) for the maintenance of anesthesia. Vecuronium was given to every patient of the three groups for intraoperative muscle relaxation. Hartmann's solution was used at a speed of 5 ml.kg-1.hr-1. Peripheral venous blood 10 ml was drawn on six occasions during and after the surgery for the measurement of NK cell activities and endocrine response as judged by plasma catecholamine and cortisol levels. NK cell activities decreased significantly on the first post-operative day in enflurane group, but no significant differences were found among three groups in NK cell activities. The data suggest that inhaled anesthetics should not be easily employed for patients with depressed immune response, malignant disease and prolonged surgery.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--4. Control of intraoperative hypertension with nicardipine

Intraoperative hypertension over 160 mmHg systolic observed during total intravenous anesthesia with droperidol, fentanyl and ketamine was treated with intravenous nicardipine in 50 surgical patients. Nicardipine was given intravenously in a bolus of either 0.5 mg or 1.0 mg to treat the intraoperative hypertension. Systolic and diastolic blood pressures decreased soon after administration of nicardipine without simultaneous sinus tachycardia. Thus rate pressure product was also reduced significantly. Neither preoperative hypertension, nor systolic blood pressure just before the administration of nicardipine had any significant relationship with hypotensive effect of intravenous nicardipine. We did not experience any adverse reaction with the drug. We conclude that intravenous nicardipine in a dose of 0.5-1.0mg can be given repeatedly to overcome hypertension observed during this method of anesthesia.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--8. Hepatic and renal functions following prolonged surgical operation of over 10 hours

Forty-four patients were studied to evaluate their postoperative hepatic and renal functions on 2nd to 4th and 7th to 10th postoperative days as judged by serum GOT, GPT, BUN and creatinine levels. The patients were divided into two groups. Twenty two patients received total intravenous anesthesia with droperidol, fentanyl and ketamine (FK group). The remaining 22 patients were given conventional enflurane-nitrous oxide anesthesia. The two groups were comparable concerning age, body weight, sex distribution, performed operation, operation time and anesthesia time. In the total intravenous group, fluid given and urine output were significantly larger than those of the enflurane group, and the amounts of blood loss and blood given tended to be greater but insignificantly in the total intravenous group than in the enflurane group. In both groups, postoperative S-GOT levels increased significantly and those of the enflurane group were significantly higher than those of the FK group on 2nd to 4th postoperative days. In the enflurane group, postoperative S-GPT levels were significantly higher, but those of the FK group were not. S-GPT on 2nd to 4th postoperative days of the enflurane group were significantly higher than those of the FK group. As to serum BUN and creatinine, no significant differences were observed between the two groups. These data suggest that FK is much more beneficial than enflurane anesthesia to protect hepatic functions, particularly when it is applied for prolonged surgical procedures.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--12. Effects on plasma complement and immunoglobulin concentrations]

Complements and immunoglobulins in the plasma are the important humoral factors to maintain immunity. As there is no study on immune response to total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK), twelve patients who underwent abdominal, neck dissection, or plastic surgery were studied to determine plasma concentrations of complements and immunoglobulins. In five patients of isoflurane group, anesthesia was induced with intravenous thiopental 5 mg.kg-1 and succinylcholine 0.8-1 mg.kg-1 and maintained with 1-2% isoflurane in nitrous oxide (50%) and oxygen (50%). The remaining seven patients of the DFK group received intravenous droperidol 0.25 mg.kg-1, fentanyl 1-2 micrograms.kg-1, ketamine 1-1.5 mg.kg-1 and succinylcholine 0.8-1 mg.kg-1 for the induction of anesthesia, and then they were given a total dose of fentanyl 5-15 micrograms.kg-1, ketamine 2 mg.kg-1.hr-1 and oxygen (30%) for the maintenance of anesthesia. Vecuronium was given intravenously as needed. Lactated Ringer's solution was used for intraoperative fluid replacement. A total of 40 ml of arterial blood was drawn on four occasions, just before the induction of anesthesia, at the recovery from anesthesia, on the third and tenth post-operative days. Plasma concentrations of complements (C3.C4) and immunoglobulins (IgG.IgA.IgM.IgD) were measured by immuno-turbidimetry. C3 concentrations in the plasma decreased significantly when the patients recovered from anesthesia, but they increased significantly on the third and tenth post-operative days in the isoflurane group. In the DFK group, they increased significantly on the tenth post-operative day only. No significant difference in the C3 concentrations was detected between two groups at any time of measurement.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of ketamine and pentazocine during total intravenous anesthesia with droperidol, pentazocine and ketamine]

Pharmacokinetics was studied in ten surgical patients who underwent various operative procedures of about 4 hours under total intravenous anesthesia with droperidol, pentazocine and ketamine (DPK). Plasma levels of ketamine, its metabolites and pentazocine were determined thirteen times during and after DPK. During anesthesia, ketamine (KO) and norketamine (KMI) levels ranged from 0.7 to 1.0 micrograms.ml-1 and from 0.09 to 0.74 micrograms.ml-1, respectively. A small amount of dehydronorketamine (KM II) was detected only 90 min after the start of DPK anesthesia. Plasma half-lives of ketamine were calculated to be 33 min for distribution phase (alpha phase) and 60 min for elimination phase (beta phase), respectively. Pentazocine levels decreased 300 min after the induction of DPK to 10% of the control level measured 5 min after its injection. Plasma half-lives of pentazocine were 60 min for alpha phase and 140 min for beta phase, respectively. The data obtained in this clinical study show that pharmacokinetics of ketamine during DPK is almost similar to that of DFK.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--10. Effects of prostaglandin E1 on the hepatic and renal functions following prolonged surgery under total intravenous anesthesia]

Twenty one patients who underwent prolonged surgical procedures over 10 hours under total intravenous anesthesia with droperidol, fentanyl and ketamine were studied to evaluate post-operative hepatic and renal functions as judged by serum levels of GOT, GPT, BUN and creatinine. They were divided into two groups. Ten patients of the PGE1 group were given PGE1 at a rate of 0.035 micrograms.kg-1.min-1 during anesthesia, and the remaining eleven of the control group were not given PGE1. The two groups were comparable concerning, age, body weight, height, operation time and anesthesia time. In the PGE1 group, significantly more intraoperative fluid was given than in the control group. The blood loss was more but insignificantly in the PGE1 group than in the control group. There was no significant difference in urine output and the amount of blood transfused between the two groups. In both groups, post-operative s-GOT and s-GPT levels were increased significantly compared with pre-operative values, but there was no significant difference between the two groups. Serum BUN levels of the 7-10 the post-operative days were increased significantly in the PGE1 group, but those of the control group were not. These data suggest that our method of total intravenous anesthesia with droperidol, fentanyl and ketamine, when applied even for prolonged surgical procedure over 10 hours, would have beneficial effects on the post-operative hepatic and renal functions.     

Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine. 14. Effect on epidural pressure]

We studied effect of total intravenous anesthesia using ketamine, fentanyl and droperidol (DFK) on epidural pressure as an index for cerebrospinal fluid pressure in six surgical patients who underwent gastrectomy. The epidural catheter was inserted on the previous day. The epidural puncture was made at Th7-12 and the tip of the catheter was located 5 cm cephalad. The epidural pressure was measured before, just after and 30 minutes after the induction. The induction dose of fentanyl was 5 micrograms.kg-1 and that of ketamine was 1 mg.kg-1. The epidural pressure at the induction decreased in significantly by 19% as compared with that before the induction. The result suggested that DFK would not increase cerebrospinal fluid pressure when the doses of ketamine and fentanyl were changed.     

Clinical study on total intravenous anesthesia with droperidol, pentazocine and ketamine]

Fifty patients underwent various surgical procedures including abdominal, orthopedic, plastic and gynecological operations under total intravenous anesthesia with ketamine, pentazocine and droperidol. Neither nitrous oxide, inhaled anesthetics nor narcotics such as fentanyl were administered to the patients. Intraoperative muscle relaxation was achieved with vecuronium and the patients were ventilated manually throughout the surgical procedures. Thirty percent of the patients developed hypertension and tachycardia, but they were easily overcome with administration of calcium ion channel blocker. Their peripheral circulation as well as urine output was well maintained. No adverse effects on the liver and kidney were observed post-operatively. Their post-operative sedation and analgesia were evaluated excellent. A few patients had strange dream as if they might have missed their way into the "pink" tunnel. The data above described suggest that this anesthetic method would deserve further detailed clinical study.     

Endocrine responses to total intravenous anesthesia with droperidol,fentanyl, and ketamine in cardiac patients

Ketamine-induced sympathetic stimulation can be inhibited by administration of sedatives such as benzodiazepines, droperidol, or opioids. We have developed total intravenous anesthesia with ketamine in combination with droperidol and fentanyl (DFK) and have used this anesthetic method in more than 4000 surgical cases. In this study, we compared DFK in cardiac surgery with isoflurane-fentanyl anesthesia (AOI-F). Fourteen patients undergoing aortocoronary artery bypass graft surgery were randomly assigned to the DFK or AOI-F groups. The endocrine responses of the patients were evaluated from the plasma, levels of cortisol, antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), and aldosterone. In both groups, anesthesia per se did not induced any significant changes in the hormones. Although cortisol and ADH increased during surgery, ANP and aldosterone did not change appreciably. All hormones were significantly elevated after the end of cardiopulmonary bypass. There were no significant differences in any of the hormones, blood pressure, and heart rate measured at different points in both groups. These results showed that DFK anesthesia as a total intravenous anesthesia deserves to be studied in more depth.     

Middle-ear pressure variations during total intravenous anesthesia with propofol, fentanyl, and ketamine

Purpose As the middle-ear cavity is one of the noncompliant gas-filled cavities, an increase in middle-ear pressure (MEP) instead of volume expansion is observed with inhalation of nitrous oxide (N₂O). Changes in MEP cause many complications, such as ear pain, temporary hearing impairment, and postoperative emesis. Therefore, we investigated changes in MEP during total intravenous anesthesia (TIVA) with propofol, fentanyl, and ketamine (PFK) and inhalation of N₂O. Methods Twelve patients were anesthetized with PFK until 60 min after the induction of anesthesia, and then N₂O (60%) inhalation was started. MEP was measured by impedance audiometry (ranging from −300 daPa to +200 daPa) at 10-min intervals during PFK, and at 2-min intervals after the inhalation of N₂O. Results MEP gradually but significantly increased from the preanesthetic value of 16±8 to 34±12 (SEM) daPa 50 min after the induction of PFK. However, MEP did not exceed the normal limit. The values of MEP in all patients were more than 200 daPa within 36 min after the start of inhalation of N₂O in oxygen. Conclusion PFK had a minimal effect on MEP, whereas addition of N₂O to PFK increased MEP dramatically. Therefore, TIVA, or at least PFK, would be a better choice for patients with middle-ear or upper-airway diseases.     

Use of continuous infusion versus intermittent bolus administration of fentanyl or ketamine during outpatient anesthesia

The intraoperative and postoperative effects of fentanyl and ketamine administered continuously by infusion were compared with those produced by conventional intermittent bolus administration in 100 patients. After a standardized induction with thiopental 4 mg/kg intravenously, patients received either fentanyl (50 micrograms boluses vs. 2 micrograms/ml infusion) or ketamine (25 mg boluses vs. 1 mg/ml infusion) as intravenous adjuvants to nitrous oxide, 70% in oxygen. With continuous infusion, the doses of fentanyl and ketamine required were decreased 45% and 43%, respectively. Similarly, the times to awakening were decreased significantly, 62% and 60%, in the fentanyl and ketamine infusion groups, respectively. Intraoperative side effects (e.g., hypoventilation, hypotension, rigidity) were less frequent in the fentanyl infusion (vs. bolus) group but did not differ in the ketamine groups. Trieger scores were consistent with a more rapid recovery in both infusion groups. Incidences of common postoperative side effects (e.g., nausea, vomiting, visual disturbances, dizziness) did not differ significantly between bolus and infusion groups. However, excessive sedation was noted in 48% and 52% of patients in the fentanyl and ketamine bolus groups, respectively, compared with 4% and 8%, respectively, in the infusion groups. Discharge times were decreased by 29% and 13% in the fentanyl and ketamine infusion groups, respectively. The author concludes that continuous infusion fentanyl (0.1 micrograms . kg-1 . min-1) or ketamine (50 micrograms . kg-1 . min-1) significantly decreases the drug dosage requirement, improves intraoperative conditions, and decreases recovery time compared with the traditional intermittent bolus technique.     

Safe management of anesthesia with total intravenous anesthesia using propofol, fentanyl and ketamine for a patient treated with intraoperative radiotherapy

A 3-year-old girl with neuroblastoma was scheduled for intraoperative radiation therapy. Prior to surgery, meetings were held to ensure the safety during transfer between the operating room and the radiation unit because those units were placed on the different floors in our hospital. In the operating room the patient was anesthetized with propofol, fentanyl and ketamine (PFK). After the resection of the tumor, the patient was moved to the radiation unit. All personnel had to leave the treatment room while the radiation was administered, which required 3 minutes. During the transfer and treatment, the following apparatus were effective to ensure the patient's safety; mobile respiratory and cardiovascular monitors, closed-circuit television to observe the monitors and patient, and a portable gas powered ventilator. The total intravenous anesthesia with PFK was used throughout all scheduled procedures. For patients treated with intraoperative radiation therapy, the administration of inhalation anesthetics should be discontinued to supply 100% oxygen, which enhances the effect of irradiation, and to avoid the complexity of the transfer with an anesthetic machine. This discontinuation, however, may cause the cardiovascular instability. It seems that total intravenous anesthesia has advantages over inhalation anesthesia for patients who undergo intraoperative radiation therapy.