Marc A. Feldman

Monitored anesthesia care with dexmedetomidine: A prospective, randomized, double-blind, multicenter trial

BACKGROUND: Dexmedetomidine (DEX) is increasingly being used as a sedative for monitored anesthesia care (MAC) because of its analgesic properties, “cooperative sedation,” and lack of respiratory depression. In this randomized, multicenter, double-blind, Phase III Food and Drug Administration study, we evaluated the safety and efficacy of two doses of DEX for sedation of patients undergoing a broad range of surgical or diagnostic procedures requiring MAC. METHODS: Three hundred twenty-six patients were randomized 2:2:1 to DEX 0.5 &mgr;g/kg, DEX 1 &mgr;g/kg, or saline placebo initial loading dose, followed by a maintenance infusion of 0.2–1.0 &mgr;g · kg−1 · h−1 of DEX (or equivalent volume of saline) titrated to a targeted level of sedation (≤4 on the Observers Assessment of Alertness/Sedation Scale [OAA/S]). Study drug was started at least 15 min before placement of regional or local anesthetic block. Midazolam was given for OAA/S >4 and fentanyl for pain. The primary end-point was the percentage of patients not requiring rescue midazolam. RESULTS: Significantly fewer patients in the 0.5- and 1-&mgr;g/kg DEX groups required supplemental midazolam compared with placebo (59.7% [80/134], 45.7% [59/129] vs 96.8% [61/63], respectively; P < 0.001) and at lower doses to achieve an OAA/S ≤4 before and during surgery compared with the saline group (1.4 and 0.9 mg vs 4.1 mg, respectively; P < 0.001, each group compared with placebo). Both DEX groups required significantly less fentanyl (84.8 and 83.6 &mgr;g vs 144.4 &mgr;g, respectively; P < 0.001, for both DEX groups versus placebo) for all surgical subtypes. Anesthesiologists indicated significantly increased ease of achieving and maintaining targeted sedation in both DEX groups compared with placebo with midazolam (P < 0.001). Patient satisfaction was significantly higher with DEX (P ≤ 0.009, both groups versus placebo). Common adverse events with DEX were protocol-defined bradycardia and hypotension that were predominately mild to moderate in severity. The incidence of clinically significant respiratory depression (defined as a respiratory rate of <8 or an oxygen saturation of <90%) was lower in DEX-treated patients (P = 0.018, for both groups versus placebo). CONCLUSIONS: DEX is an effective baseline sedative for patients undergoing MAC for a broad range of surgical procedures providing better patient satisfaction, less opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl.

Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery

OBJECTIVE To estimate the risks and benefits associated with continuation of anticoagulants or antiplatelet medication use before cataract surgery. DESIGN Prospective cohort study. PARTICIPANTS Patients 50 and older scheduled for 19,283 cataract surgeries at nine centers in the United States and Canada between June 1995 and June 1997. INTERVENTION None. MAIN OUTCOME MEASURES Intraoperative and postoperative (within 7 days) retrobulbar hemorrhage, vitreous or choroidal hemorrhage, hyphema, transient ischemic attack (TIA), stroke, deep vein thrombosis, myocardial ischemia, and myocardial infarction. RESULTS Before cataract surgery 24.2% and 4.0% of patients routinely used aspirin and warfarin, respectively. Among routine users, 22.5% of aspirin users and 28.3% of warfarin users discontinued these medications before surgery. The rates of stroke, TIA, or deep vein thrombosis were 1.5/1000 among those who did not use aspirin or warfarin and 3.8/1000 surgeries among routine users of aspirin and warfarin who continued their medication before surgery. The rate was 1 event per 1000 surgeries among those who discontinued aspirin use (relative risk = 0.7, 95% confidence interval = 0.1-5.9). There were no events among warfarin users who discontinued use. The rates of myocardial infarction or ischemia were 5.1/1000 surgeries (aspirin) and 7.6/1000 surgeries (warfarin) among routine continuous users and no different from those of routine users who discontinued use. CONCLUSIONS The risks of medical and ophthalmic events surrounding cataract surgery were so low that absolute differences in risk associated with changes in routine anticoagulant or antiplatelet use were minimal.

Adverse intraoperative medical events and their association with anesthesia management strategies in cataract surgery

OBJECTIVE To compare adverse medical events by different anesthesia strategies for cataract surgery. DESIGN Prospective cohort study. PARTICIPANTS Patients 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada between June 1995 and June 1997. INTERVENTION Local anesthesia applied topically or by injection, with or without oral and intravenous sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl). MAIN OUTCOME MEASURES Intraoperative and postoperative adverse medical events. RESULTS Twenty-six percent of surgeries were performed with topical anesthesia and the remainder with injection anesthesia. There was no increase in deaths and hospitalizations associated with any specific anesthesia strategy. No statistically significant difference was observed in the prevalence of intraoperative events between topical and injection anesthesia without intravenous sedatives (0.13% and 0.78%, respectively). The use of intravenous sedatives was associated with a significant increase in adverse events for topical (1.20%) and injection anesthesia (1.18%), relative to topical anesthesia without intravenous sedation. The use of short-acting hypnotic agents with injection anesthesia was also associated with a significant increase in adverse events when used alone (1.40%) or in combination with opiates (1.75%), sedatives (2.65%), and with the combination of opiates and sedatives (4.04%). These differences remained after adjusting for age, gender, duration of surgery, and American Society of Anesthesiologists risk class. CONCLUSIONS Adjuvant intravenous anesthetic agents used to decrease pain and alleviate anxiety are associated with increases in medical events. However, cataract surgery is a safe procedure with a low absolute risk of medical complications with either topical or injection anesthesia. Clinicians should weigh the risks and benefits of their use for individual patients.

Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography

[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769–5,920 Ci/mmol) and low (27–80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1–1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 ± 0.2 (occipital cortex) to 8.6 ± 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 ± 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 ± 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 ± 0.5 (occipital cortex) to 20.6 ± 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 ± 0.17 nM.

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [11C]Flumazenil

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration (Bmax) and equilibrium dissociation constant (Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/k2 estimate of 0.68 ± 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma (f1) was determined for each study (high SA f1: 0.50 ± 0.03; low SA f1: 0.48 ± 0.05). The free fraction in brain (f2) was calculated using the inhibition K1/k2 ratio and each volunteers mean f1 value (f2 across volunteers = 0.72 ± 0.03 ml/ml). Three methods (Methods I–III) were examined. Method I determined five kinetic parameters simultaneously [K1, k2, k3 (= konf2Bmax), k4, and konf2/SA] with no a priori constraints. An average kon value of 0.030 ± 0.003 nM−1 min−1 was estimated for receptor-rich regions using Method I. In Methods II and III, the konf2/SA parameter was specifically constrained using the Method I value of kon and the volunteers values of f2 and low SA (Ci/μmol). Four parameters were determined simultaneously using Method II. In Method III, K1/k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 ± 25 nM in the occipital cortex, 64 ±18 nM in the cerebellum, and 38 ± 5.5 nM in the thalamus; the average Kd was 8.9 ± 1.0 nM (five brain regions).

Injectable versus topical anesthesia for cataract surgery: Patient perceptions of pain and side effects

OBJECTIVE To compare patient reports of intraoperative pain and postoperative side effects by different anesthesia strategies for cataract surgery. DESIGN Prospective cohort study. PARTICIPANTS Men and women 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada from June 1995 through June 1997. INTERVENTION Topical anesthesia or anesthesia with injection, with or without sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl). MAIN OUTCOME MEASURES Patient ratings of intraoperative pain, satisfaction with pain management, and early postoperative side effects (drowsiness, nausea, vomiting, or a combination thereof). RESULTS Twenty-six percent of surgeries were performed using topical anesthesia alone, and the remainder were performed with peribulbar, retrobulbar, or facial nerve block, or a combination thereof. Local anesthesia by injection with sedatives and diphenhydramine resulted in the lowest reporting of any intraoperative pain (1.3%), with postoperative drowsiness (9.6%) and nausea, vomiting, or both (1.5%) comparable with those administered topical anesthesia alone. Among those receiving topical anesthesia, use of sedatives and opioids reduced reports of any pain during surgery by 56% (95% confidence interval [CI], 34%, 70%), but increased nausea and vomiting (odds ratio, 2.27; 95% CI, 1.26, 4.09) compared with those administered topical anesthesia alone, after adjusting for age, gender, race, American Society of Anesthesiologists risk class, self-reported health status, and duration of surgery. Among those receiving local injections, use of opioids reduced reports of any pain among those receiving sedatives by 37% (95% CI, 15%, 54%), but did not increase postoperative side effects. The use of diphenhydramine among those receiving sedatives decreased reports of any pain by 59% (95% CI, 33%, 75%) and also reduced drowsiness and nausea and vomiting by 57% (95% CI, 48%, 65%) and by 60% (95% CI, 36%, 75%), respectively. Use of hypnotics with sedatives was associated with increased reports of any pain during surgery and increased nausea and vomiting after surgery. CONCLUSIONS Patient reports of any pain during cataract surgery (5%) and postoperative side effects (16% drowsiness and 4% nausea and vomiting) were low, but varied by anesthesia strategy. Patient perceptions of pain and side effects can be helpful in guiding the appropriate choice of anesthesia strategy.

The value of routine preoperative medical testing before cataract surgery.

BACKGROUND Routine preoperative medical testing is commonly performed in patients scheduled to undergo cataract surgery, although the value of such testing is uncertain. We performed a study to determine whether routine testing helps reduce the incidence of intraoperative and postoperative medical complications. METHODS We randomly assigned 19,557 elective cataract operations in 18,189 patients at nine centers to be preceded or not preceded by a standard battery of medical tests (electrocardiography, complete blood count, and measurement of serum levels of electrolytes, urea nitrogen, creatinine, and glucose), in addition to a history taking and physical examination. Adverse medical events and interventions on the day of surgery and during the seven days after surgery were recorded. RESULTS Medical outcomes were assessed in 9408 patients who underwent 9626 cataract operations that were not preceded by routine testing and in 9411 patients who underwent 9624 operations that were preceded by routine testing. The most frequent medical events in both groups were treatment for hypertension and arrhythmia (principally bradycardia). The overall rate of complications (intraoperative and postoperative events combined) was the same in the two groups (31.3 events per 1000 operations). There were also no significant differences between the no-testing group and the testing group in the rates of intraoperative events (19.2 and 19.7, respectively, per 1000 operations) and postoperative events (12.6 and 12.1 per 1000 operations). Analyses stratified according to age, sex, race, physical status (according to the American Society of Anesthesiologists classification), and medical history revealed no benefit of routine testing. CONCLUSIONS Routine medical testing before cataract surgery does not measurably increase the safety of the surgery.