Nathan L. Pace

Frequent hypoxemia and apnea after sedation with midazolam and fentanyl.

More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical procedures. We investigated the respiratory effects of midazolam (0.05 mg.kg-1) and fentanyl (2.0 micrograms.kg-1) in volunteers. The incidence of hypoxemia (oxyhemoglobin saturation less than 90%) and apnea (no spontaneous respiratory effort for 15 s) and the ventilatory response to carbon dioxide were evaluated. Midazolam alone produced no significant respiratory effects. Fentanyl alone produced hypoxemia in half of the subjects and significant depression of the ventilatory response to CO2, but did not produce apnea. Midazolam and fentanyl in combination significantly increased the incidence of hypoxemia (11 of 12 subjects) and apnea (6 of 12 subjects), but did not depress the ventilatory response to CO2 more than did fentanyl alone. Adverse reactions linked to midazolam and reported to the Department of Health and Human Services highlight apnea- and hypoxia-related problems as among the most frequent adverse reactions. Seventy-eight per cent of the deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered. All but three of the deaths associated with the use of midazolam occurred in patients unattended by anesthesia personnel. We conclude that combining midazolam with fentanyl or other opioids produces a potent drug interaction that places patients at a high risk for hypoxemia and apnea. Adequate precautions, including monitoring of patient oxygenation with pulse oximetry, the administration of supplemental oxygen, and the availability of persons skilled in airway management are recommended when benzodiazepines are administered in combination with opioids.

Advances in and limitations of up-and-down methodology : A précis of clinical use, study design, and dose estimation in anesthesia research

Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose–response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose–response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose—the target dose—associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.

Comparison of Sufentanil-O2 and Fentanyl-O2 for Coronary Artery Surgery

The cardiovascular responses, speed of anesthetic induction, incidence of chest wall rigidity, need for anesthetic supplements (phe-notolamine, N2O, and nitroprusside) to control intraoperative hy-pertension and speed of postoperative recovery were measured and compared in 37 patients undergoing coronary artery bypass grafting (CABG) operations with fentanyl-O2 (Group II) or sufentanil-O2 (Group II) anesthesia. After lorazepam-atropine premedication and pancuronium pretreatment, fentanyl was administered intravenously at 400 μg/min and sufentanil at 300 μg/min until patients were unconscious; at this time they were given succinylcholine and their tracheas were intubated. After intubation an amount of fentanyl or sufentanil equal to the dose producing unconsciousness was infused over the next 30 min, at which time the operation began. Additional fentanyl or sufentanil was given whenever systolic arterial blood pressure (SBP) increased more than 15 per cent of preanesthetic values. When three successive supplemental doses of the narcotic failed to effectively decrease SBP, phentolamine was used to control pressure before and during bypass; after bypass N2O (25–50 per cent) or, if N2O was ineffective, nitroprusside was used. Average time of induction was 4.6 · 0.5 and 1.3 · 0.3 min (mean · SD) for fentanyl and sufentanil, respectively. Chest wall rigidity occurred in 22 per cent of patients receiving fentanyl and 28 per cent of those receiving sufentanil. Total doses of fentanyl and sufentanil required for the entire operation were 122 · 15 and 12.9 · 0.5 (mean · SD) μg/kg, respectively. Heart rate, cardiac output, and mean right atrial pressure remained unchanged throughout the study in both groups. SBP was reduced slightly in both groups during induction but returned to control values prior to incision. Group II patients experienced no significant change in SBP after incision, sternotomy, or sternal spread, whereas SBP became significantly increased following sternal spread in patients given fentanyl. Phentolamine was required in 42 and 47 per cent of Group I patients before and during bypass, respectively, but in only 6 and 11 per cent of Group II patients. Fifty-three per cent of Group I patients required N2O, and 21 per cent required nitroprusside after bypass for blood pressure control. Only 11 per cent of Group II required N2O and 6 per cent required nitroprusside post-bypass. Hypertension requiring supplementation with phentolamine, N2O, or nitroprusside occurred more frequently in patients not taking preoperative beta-adrenergic blockers than in those taking these drugs in Group I. Hypertension requiring supplementaion never occurred in patients in Group II taking beta-blockers. The results of this study demonstrate that sufentanil may be a superior narcotic to fentanyl for use in patients undergoing CABG operations. The authors’ data also indicate that preoperative use of beta-adrenergic blocking durgs reduceds intraoperative hypertension with narcotic-oxygen anesthesia.

Anesthetic techniques during surgical repair of femoral neck fractures. A meta-analysis.

Fracture of the hip typically occurs in older women. These patients usually have serious accompanying chronic illnesses. There is a difference of opinion as to the choice of regional versus general anesthesia for surgery in these patients. This meta-analysis compared survival of patients with traumatic femoral neck fractures undergoing operative repair during regional or general anesthesia. The data sources were articles comparing regional and general anesthesia from peer reviewed journals. Thirteen randomized controlled trials were found. Besides 1-month mortality, variables used were estimated operative blood loss and the incidence of deep venous thrombosis. For dichotomous outcomes, two effect measures were calculated: the difference in probabilities and the odds ratio. For blood loss, a continuous variable, the effect measure was the mean difference in blood loss. A random-effects Bayesian meta-analysis was used to combine study data, estimate parameters and create 95% confidence intervals. Only the incidence of deep venous thrombosis was clearly greater for patients receiving general anesthesia, being 31 percentage points higher than for patients receiving regional anesthesia. By the odds ratio, deep venous thrombosis was almost four times more likely following general anesthesia. There was no difference in estimated operative blood loss. By probability difference, mortality was a non-significant 2.7 percentage points less following regional anesthesia. By odds ratio effect measure, death was 1.5 times more likely following general anesthesia, but the lower bound of the 95% confidence interval was close to 1. Meta-analysis does not allow a conclusion that important differences in mortality exist between regional and general anesthesia for traumatic hip fracture surgery.

Respiratory Effects of Clonidine Alone and Combined with Morphine, in Humans

Because only limited and controversial data exist concerning the respiratory effects of clonidine in humans, the authors evaluated the respiratory effects of clonidine alone and in combination with morphine, in 12 healthy adult males. Subjects received clonidine (0.3-0.4 mg orally), morphine (0.21 mg/kg intramuscularly), or the same doses of the two drugs combined, at three separate sessions in a randomized fashion. The study was balanced for all possible sequences of drug administration. Blood pressure, heart rate, hemoglobin oxygen saturation via finger pulse oximetry, and ventilatory and occlusion pressure responses to CO2 were obtained before and 20, 40, 60, 90, 120, 180, 240, 300, and 360 min after administration of drug or drug combination. Systolic blood pressure decreased significantly only in the clonidine and clonidine plus morphine groups (P less than 0.05). Hemoglobin oxygen saturation decreased by a statistically significant (P less than 0.05), though clinically minor, degree only in the morphine or morphine plus clonidine groups. Clonidine alone did not depress the slope of either the ventilatory or the occlusion pressure response to CO2. In addition, clonidine did not significantly worsen morphine-induced depression of the slope of the ventilatory and occlusion pressure responses in the drug combination group. Both the ventilatory and occlusion pressure responses to CO2 were shifted to the right in all three drug groups (P less than 0.05) but were shifted to a significantly lesser degree by clonidine alone than by morphine and morphine plus clonidine. In healthy young adult males, clonidine alone produces little respiratory depression and does not significantly potentiate morphine-induced respiratory depression.

A Comparison of Topical and Retrobulbar Anesthesia for Cataract Surgery

PURPOSE To evaluate and compare the efficacy of topical and retrobulbar anesthesia for cataract extraction with intraocular lens implantation. METHODS One hundred thirty-eight patients prospectively were assigned to the topical (group 1; n = 69) or retrobulbar (group 2; n = 69) anesthesia groups by permuted block restricted randomization. Group 1 received topical 0.75% bupivacaine and intravenous midazolam and fentanyl for anesthesia. Group 2 received intravenous methohexital followed by retrobulbar block with an equal mixture of 2% lidocaine and 0.75% bupivacaine plus hyaluronidase (150 U). A visual pain analogue scale was used to assess the degree of pain during the administration of anesthesia, during surgery, and post-operatively. The degree to which eye movement, touch, and light caused patient discomfort was assessed. Complications and surgical conditions were recorded. RESULTS There was no difference in the surgical conditions (P = 0.5) or pain during surgery (P = 0.35) between the two groups. There was more discomfort during administration of topical anesthesia (P < 0.0001) and postoperatively (P < 0.05) in the topical group. Chemosis, subconjunctival hemorrhage, and eyelid hemorrhage were seen almost exclusively in the retrobulbar group. One patient in group 2 had a retrobulbar hemorrhage. Although eyeball movement and squeezing of the eyelids were present more frequently in the topical group, neither was a problem to the surgeon. CONCLUSION Topical anesthesia can be used safely for cataract extraction. The degree of patient discomfort is only marginally higher during administration of the anesthesia and postoperatively. However, surgical training and patient preparation are the keys to the safe use of topical anesthesia.

Fentanyl and Sufentanil Increase Intracranial Pressure in Head Trauma Patients

Although opioids frequently are administered to patients with severe head trauma, the effects of such drugs on intracranial pressure are controversial. Nine patients with severe head trauma were studied for the effects of fentanyl and sufentanil on intracranial pressure (ICP). In all patients, ICP monitoring was instituted before the study. Full neuromuscular blockade was achieved with vecuronium bromide before the administration of either fentanyl (3 micrograms.kg-1) or sufentanil (0.6 microgram.kg-1) as an intravenous bolus over a 1-min period in a masked and random fashion. Patients received the other opioid in the same fashion 24 h later. Arterial blood pressure, heart rate, and ICP were recorded continuously for the 1 h after drug administration. Fentanyl was associated with an average ICP increase of 8 +/- 2 mmHg, and sufentanil with an increase of 6 +/- 1 mmHg. These increases were statistically significant. Both drugs produced clinically mild decreases in mean arterial blood pressure (fentanyl, 11 +/- 6 mmHg; sufentanil, 10 +/- 5 mmHg) that nevertheless were statistically significant. No significant changes in heart rate occurred. These results indicate that modest doses of potent opioids can significantly increase ICP in patients with severe head trauma.

Anesthetic induction with fentanyl.

The efficacy of fentanyl, 30 μg/kg, was evaluated as an anesthetic induction agent in 72 ASA I–III patients scheduled for 2–4-hr operations. The effect of preinduction pretreatment with pancuronium and/or diazepam and the incidence of loss of consciousness (anesthesia), recall, rigidity, abnormal muscle movements, and hemodynamic changes were documented. Seventy-four percent of all patients became anesthetized. Diazepam pretreatment enhanced but did not ensure success of anesthetic induction. There was a significant correlation between age and the incidence of unconsciousness (P = 0.0287) and all patients over 60 yr old were anesthetized with 30 μg/kg of fentanyl. The incidence and severity of rigidity was reduced by pancuronium (P = 0.0002) but not by diazepam pretreatment. However, pancuronium plus diazepam produced a significant reduction in the incidence of rigidity when compared to pancuronium alone (P = 0.031). A significant positive correlation between age and the incidence of rigidity (P = 0.003) was found. Six patients had focal and one patient global tonic-clonic abnormal muscle movements. Diazepam but not pancuronium significantly decreased both heart rate (P = 0.05) and blood pressure (P = 0.04). Seventeen patents required reversal of narcotic effect to restore adequate spontaneous respiration after surgery. No patient required postoperative mechanical ventilatory assistance. The results of this study demonstrate that 30 μ/kg of fentanyl is not a reliable anesthetic induction dose in patients less than 60 yr old. Both age arid premedication enhance the anesthetic capabilities of induction with fentanyl. However, increasing age is associated with an increased incidence of rigidity and diazepam pretreatment may compromise hemodynamic stability. Significant postoperative respiratory depression can occur with 30 μg/kg of fentanyl used for induction of anesthesia in operations lasting 2–4 hr.

Differences in magnitude and duration of opioid-induced respiratory depression and analgesia with fentanyl and sufentanil.

The magnitude and duration of analgesia and respiratoy depression induced by fentanyl (1.0, 2.0, and 4.0 μg/kg) and sufentanil (0.1, 0.2, and 0.4 μg/kg) after intravenous administration over 30 s were measured in 30 healthy young adult male volunteers divided into three groups and studied in a double-blind, randomized fashion. Each volunteer received one dose of fentanyl or sufentanil and no sooner than 48 h later, the corresponding equipotent dose of the other opioid. End-tidal CO2 and ventilatory and occlusion pressure responses to CO2 rebreathing were used to measure drug-induced respiratory effects. Analgesic effects were assessed by changes in the pain threshold to electric shock applied to the forearm. Plasma levels of fentanyl and sufentanil were measured by radioimmunoassay. Testing and sampling intervals were 5, 30, 60, 90, 120, 240, 300, and 360 min after drug administration.The magnitude and duration of depression of the ventilatoy and occlusion pressure response were significantly less with sufentanil compared with fentanyl, irrespective of dose. Ventilatory and occlusion pressure responses returned to control values by 30 and 30 min, respectively, after sufentanil and by 240 and 220 min, respectively, after fentanyl. Statistically significant elevations of the pain threshold were, however, greater and longer lasting after sufentanil compared with fentanyl. Pain threshold returned to control values 180 min after sufentanil but only 90 min after fentanyl. These results suggest that sufentanil may provide better patient comfort with less respiratory depression than does fentanyl.

Transdermal Scopolamine Reduces Nausea and Vomiting After Outpatient Laparoscopy

The authors evaluated the effect of transdermal scopolamine on the incidence of postoperative nausea, retching, and vomiting after outpatient laparoscopy in a double-blind, placebo-controlled study. A Band-Aid-like patch containing either scopolamine or placebo was placed behind the ear the night before surgery. Anesthesia was induced with fentanyl (0.5-2 micrograms/kg iv), thiopental (3-5 mg/kg iv), and succinylcholine (1-1.5 mg/kg iv) and maintained with isoflurane (0.2-2%) and nitrous oxide (60%) in oxygen. Scopolamine-treated patients had less nausea, retching, and vomiting compared with placebo-treated patients (P = 0.0029). Severe nausea and/or vomiting was present in 62% of the placebo group but only 37% of those getting the scopolamine patch. Repeated episodes of retching and vomiting were also less frequent in the scopolamine group compared with the placebo group (23% vs. 41%; P = 0.0213) as was the need for additional antiemetic therapy (13% vs. 32%; P = 0.0013). Patients in the scopolamine group were also discharged from the hospital sooner (4 +/- 1.3 vs. 4.5 +/- 1.5 h; P = 0.0487). Side effects were more frequent among those patients treated with the scopolamine patch (91% vs. 45%; P less than 0.05) but were not troublesome. The authors conclude that transdermal scopolamine is a safe and effective antiemetic for outpatients undergoing laparoscopy.