J. Lance Lichtor

Liver transplantation with reduced-size donor organs

Orthotopic liver transplantation (OLT) of the pediatric patient is often limited by the availability of a size-matched donor organ. Use of reduced liver transplantation (RLT) can increase the proportion of candidates transplanted and may reduce overall mortality. We report herein the initial clinical application of RLT in the United States. Indications for RLT included fulminant hepatic failure (n=2), acute hepatic artery thrombosis (n=3), and chronic liver disease unresponsive to inpatient support and more than 30 days on transplant list (n=4). Donor hepatectomy was performed using standard techniques. Formal hepatic resection was performed ex-vivo to create a size-matched graft, from the larger donor organ, which was implanted in the orthotopic position. Between 11/84 and 4/87, 70 pediatric patients were evaluated for OLT, and 33 of these were transplanted. During this period only 5 patients (7%) died awaiting OLT. Of 33 patients treated at the University of Chicago, 5 received RLT. Donor: recipient weight ratios ranged from 2:1 to 8.1:1. For RLT median operative blood loss was 1.7 blood volumes (range 0.5–11.7) with an operative time of 9.3+3.5 hr. Acceptable early graft function was observed in five patients, all of whom were discharged from the hospital. Four of these five patients are alive between 2 and 48 months after transplantation. Marginal graft function with cholestasis and coagulopathy was associated with acute intracranial hemorrhage and neurologic death in one case. One patient died intraoperatively with non-function caused by the use of a liver from a donor with steatosis and a poor size match. Another patient died on day 5 with primary nonfunction and persistant hemorrhage. Systemic cytomegalovirus infection was the cause of death in the other two cases. RLT can provide life-sustaining liver function in urgent clinical settings. The graft can serve as a temporary or permanent liver replacement. With evolution of the technique RLT could eventually be offered to more elective candidates and increase the utilization of available donors by reducing size limitations in OLT.

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0–24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0–24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0–48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

Right heart dysfunction, pulmonary embolism, and paradoxical embolization during liver transplantation. A transesophageal two-dimensional echocardiographic study.

In 16 adult patients, we performed continuous intraopcrative two-dimensional transesophageal echocardiography (2DTEE) to help elucidate the mechanism of rnyocardial dysfunction that accompanies liver transplantation. In 4 of the 16 patients “paradoxical” motion of the interventricular septum consistent with right ventricular failure was seen. An additional three of the 16 patients showed right atrial enlargement and right-to-left deviation of the interatrial septum. Two patients showed evidence of paradoxical embolization (one of whom had right ventricular and right atrial enlargement), and a third patient (who had right atrial enlargement) embolized a large right atrial thrombus into the pulmonary circulation. Two-dimensional transesophageal echocardiography demonstrated that isolated right ventricular failure might account for some of the hemodynamic instability seen during liver transplantation. Venous, pulmonary, and paradoxical embolization of air and thrombi documented by transesophageal echocardiography likely contribute to right heart failure.

Clinical recovery and psychomotor function after brief anesthesia with propofol or thiopental

Propofol, the new intravenous anesthetic agent, is generally used in outpatient anesthesia with expectations of fast recovery. We assessed recovery from anesthesia in a double-blind, crossover, controlled manner in 12 healthy volunteers using clinical tests during the first hour and several psychomotor tests 0.5, 1, 3, 5, and 7 h after brief anesthesia with propofol (2.5 mg/kg and 1.0 mg/kg 3 min later) or thiopental (5.0 mg/kg and 2.0 mg/kg 3 min later). Subjects were able to respond to command, sit, and stand steadily significantly faster (P less than 0.05) after propofol (time until standing steadily 33 +/- 7 min; mean +/- SD) when compared to thiopental anesthesia (time until standing steadily 62 +/- 29 min; mean +/- SD). Psychomotor performance remained significantly worse (P less than 0.05 to P less than 0.001) compared to control for 1 h after propofol and for 5 h after thiopental anesthesia. We conclude that the rapid and complete recovery makes propofol a suitable anesthetic for patients undergoing brief ambulatory surgery.

Indirect Measurement of Blood Pressure in Neonates and Infants Utilizing an Automatic Noninvasive Oscillometric Monitor

An indirect automatic blood pressure (BP) monitor utilizing the oscillometric principle and a microprocessor is now available for use in infants. This device was evaluated by comparing its systolic BP determinations with simultaneous Doppler systolic BP determinations in neonates and infants undergoing general anesthesia. Five determinations each were made in 125 babies who were grouped according to age. Correlation coefficients of the paired BP determinations were: in 27 premature neonates, r = 0.82; in 24 term neonates, r = 0.93; in 47 infants aged 5 to 13 weeks, r = 0.92; and in 27 infants aged 14 to 26 weeks, r = 0.94. The device was also evaluated by comparing its BP determinations with those of indwelling arterial lines present in 20 additional infants (five determinations each). Correlation coefficients were 0.96 for systolic determinations and 0.94 for diastolic determinations. No morbidity or significant technical problems were noted. It was concluded that the device is an accurate, safe, and easy noninvasive method for monitoring BP in infants.

Subjective and Psychomotor Effects of Sub anesthetic Doses of Propofol in Healthy Volunteers

Propofol is increasingly being used in medical and surgical procedures in which conscious sedation of the patient is desired. The mood-altering and psychomotor effects of subanesthetic concentrations of propofol have not been well characterized. Therefore, we examined the effects of intravenous infusions of different subanesthetic doses of propofol on mood and psychomotor/cognitive performance in healthy volunteers (n = 10). A prospective, randomized, placebo-controlled, double-blind, crossover design was used in which subjects first were administered an intravenous loading dose of propofol or placebo (Intralipid) and then were infused over a 20-min period with a given dose of propofol or placebo. Each subject received placebo (Intralipid loading dose and infusion), low-dose propofol (0.08 mg/kg loading dose and 0.5 mg.kg-1.h-1 infusion), moderate-dose propofol (0.16 mg/kg loading dose and 1.0 mg.kg-1.h-1 infusion), and high-dose propofol (0.32 mg/kg loading dose and 2.0 mg.kg-1.h-1 infusion) in four sessions spaced approximately 1 week apart. Propofol induced changes in mood in a dose-related fashion. Some of these mood-altering effects lingered for as long as 30 min after termination of the infusion, but, in general mood had returned to baseline levels 1 h after termination of the infusion. Intralipid induced no changes in mood during the infusion period. Psychomotor functioning was impaired during, and anterograde amnesia was present after, the high-dose propofol infusion. These results suggest that propofol as a sedative has a spectrum of effects that are well-suited for ambulatory surgery (e.g., sedation, amnesia, and rapid and complete recovery).

Subjective and behavioral responses to intravenous fentanyl in healthy volunteers

Fentanyl is a mu opiate agonist which is occasionally abused by medical personnel who have ready access to the drug. We examined in healthy volunteers (N=13) the subjective and psychomotor-impairing effects of intravenous fentanyl (0–100 µg/70 kg). A randomized, placebo-controlled, crossover design was used in which subjects were injected with 0, 25 (N=6), 50 and 100 µg/70 kg fentanyl in a double-blind fashion. Subjects completed several questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 3 h after drug injection. Subjects also completed several psychomotor tests at these times. Some aspects of psychomotor functioning (e.g., eye-hand coordination) were impaired by fentanyl. Fentanyl produced dose-related increases in ratings of “high” and “sedated,” but also tended to produce dysphoria and somatic symptomatology. Most subjects reported liking the effects of the two higher doses of fentanyl for at least a brief time after injection, but they varied widely in their liking ratings across the 3-h post-drug injection period. Despite the transient increases in liking ratings, fentanyl did not increase scores on a widely-used measure of drug-induced euphoria (morphine-benzedrine group scale of the Addiction Research Center Inventory). The present results suggest that some medical personnel who experiment with fentanyl may like it, and thus be at increased risk for abusing the drug in the future.

Propofol at conscious sedation doses produces mild analgesia to cold pressor-induced pain in healthy volunteers.

STUDY OBJECTIVE To determine whether subanesthetic doses of propofol have analgesic effects in healthy volunteers. DESIGN Prospective, double-blind, placebo-controlled, randomized, crossover trial. SETTING Human psychomotor performance laboratory within our anesthesia and critical care department. SUBJECTS 12, non-drug abusing volunteers, aged 22 to 38 years. INTERVENTIONS Five drug conditions were used in which a loading injection was followed by a 20-minute infusion period: placebo [saline (Intralipid)] injection, Intralipid infusion; propofol 0.125 mg/kg injection, propofol 12.5 mcg/kg/min infusion; propofol 0.25 mg/kg injection, propofol 25 mcg/kg/min infusion; propofol 0.5 mg/kg injection, propofol 50 mcg/kg/min infusion; fentanyl 1.4 mcg/kg injection (positive control), Intralipid infusion. Five minutes into the infusion period and 115 minutes after the infusion period was terminated, subjects immersed their forearms in ice-cold water for three minutes while pain assessments were recorded. MEASUREMENTS AND MAIN RESULTS Propofol at the two higher doses during part of the first immersion produced a significant reduction (p < 0.05) in pain intensity and bothersomeness ratings. However, relative to fentanyl, the analgesia was mild. Propofol did not affect any ratings on the 15-item short-form McGill Pain Questionnaire, whereas fentanyl reduced 10 of the ratings. CONCLUSION Our laboratory results are consistent with the commonly accepted clinical practice of supplementing propofol with an opioid in conscious sedation procedures to provide a satisfactory level of pain relief.

Cardiovascular effects of inhalation induction with isoflurane in infants.

We evaluated hemodynamic changes during inhalation induction of isoflurane anesthesia in 60 healthy infants aged 5-26 weeks who were randomly divided into two groups of 30 patients each. In group 1 anesthesia was induced using isoflurane in concentrations that were increased to 3.5%. In group 2, 0.02 mg/kg of atropine was given intramuscularly before induction of anesthesia, as in group 1. In both groups, N2O (3 L/min) and O2 (2 L/min) were administered using a nonrebreathing system. Heart rate (HR) and blood pressure (BP) were recorded at 1-min intervals for 20 min. HR decreased 32% in group 1 and 20% in group 2; BP decreased 40% in group 1 and 38% in group 2. During isoflurane induction in infants, both HR and BP are depressed. Premedication with atropine minimizes the depression of HR, but does not affect the change in BP.We evaluated hemodynamic changes during inhalation induction of isoflurane anesthesia in 60 healthy infants aged 5–26 weeks who were randomly divided into two groups of 30 patients each. In group 1 anesthesia was induced using isoflurane in concentrations that were increased to 3.5%. In group 2, 0.02 mg/kg of atropine was given intramuscularly before induction of anesthesia, as in group 1. In both groups, N2O (3 L/min) and O2 (2 L/min) were administered using a nonrebreathing system. Heart rate (HR) and blood pressure (BP) were recorded at 1-min intervals for 20 min. HR decreased 32% in group 1 and 20% in group 2; BP decreased 40% in group 1 and 38% in group 2. During isoflurane induction in infants, both HR and BP are depressed. Premedication with atropine minimizes the depression of HR, but does not affect the change in BP.

Assessing the behavioral effects and abuse potential of propofol bolus injections in healthy volunteers

Propofol is a recently introduced intravenous anesthetic agent, commonly administered to surgical patients because it induces anesthesia smoothly (i.e., provides loss of consciousness rapidly and usually with no complications) and is associated with rapid recovery. Propofol has psychoactive effects that could be construed as pleasant, although little abuse liability testing has been done on this agent in humans. Accordingly, we examined various effects of this agent at different subanesthetic doses (0.2-0.6 mg/kg) in order to characterize this drugs abuse potential (for recreational use or potential for diversion). Using a double-blind, randomized, crossover design, healthy normal volunteers (N = 10) were injected intravenously with the drug or with placebo. Before the injection and for up to 1 h afterwards, mood (including drug liking), memory and psychomotor performance were assessed. Propofol impaired memory and psychomotor performance and produced changes in 10 of 20 VAS mood ratings. Although there was variability in self-reported drug liking, some subjects clearly liked the effects of propofol, especially at the two higher doses. At the debriefing interview held after completion of the study, five subjects said if they had to participate in one more session in which they were given a choice between being injected with the highest dose (0.6 mg/kg) or a placebo, they would choose propofol. These preliminary results suggest that this agent may have some potential for abuse/diversion and perhaps stricter accountability procedures should be established for this drug in settings where general anesthesia or conscious sedation procedures are done.