Michael A. Ashburn

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.

Management of chronic pain

Chronic pain is a common condition for which patients seek care from various health-care providers. This type of pain causes much suffering and disability and is frequently mistreated or undertreated. Patients who present for evaluation for chronic pain should undergo a careful assessment before therapy. Patients with chronic pain commonly experience depression, sleep disturbance, fatigue, and decreased overall physical and mental functioning. They frequently require an interdisciplinary model of care to allow care givers to address the multiple components of the patients pain experience. After a careful evaluation, therapy may include medication, nerve blocks, active physical therapy, behavioural interventions, and assistance with vocational evaluation and training. Less frequently therapy may include placement of implantable devices to alter the pain experience. These patients suffer from a chronic condition and often require long-term care, with frequent reassessment and adjustment of therapy. Although cure is possible, it is also infrequent. Therefore, therapy is provided with the aim of decreasing pain and suffering while improving physical and mental functioning.

Absorption and Bioavailability of Oral Transmucosal Fentanyl Citrate

Oral transmucosal fentanyl citrate (OTFC) is a novel, noninvasive dosage form of fentanyl used to provide children and adults with sedation, anxiolysis, and analgesia. In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 micrograms/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 h for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl, clearance (mean +/- standard deviation) was 0.67 +/- 0.15 l/min; volume of distribution at steady state was 287 +/- 79 l; and the terminal elimination half-life was 425 +/- 102 min. Peak plasma concentrations of fentanyl were higher (3.0 +/- 1.0 vs. 1.6 +/- 0.6 ng/ml, P = 0.01) and occurred sooner (22 +/- 2.5 vs. 101 +/- 48.8 min, P = 0.003) after OTFC than after oral solution administration. Plasma concentrations of fentanyl after OTFC decreased rapidly, to less than 1.0 ng/ml within 75-135 min after the beginning of administration. Peak absorption rate was greater (11.1 +/- 4.3 vs. 3.6 +/- 2.1 micrograms/min, P = 0.004) and occurred much sooner after OTFC than after oral solution administration (19 +/- 2.6 vs. 87.5 +/- 38.1 min, P = 0.001). Systemic bioavailability was greater after OTFC administration than after the oral solution (0.52 +/- 0.1 vs. 0.32 +/- 0.1, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cost of Opioid-Related Adverse Drug Events in Surgical Patients

Opioids have demonstrated efficacy and often are drugs of choice in the management of postoperative pain. However, their use is often limited by adverse drug events (ADEs). The objective of this study was to determine the ADE rate in adult surgical patients who received opioids and the impact of opioid ADEs on length of stay (LOS), costs, and mortality. A hospital-based computerized system detected potential ADEs. Adult patients were selected if they received at least one dose of opioid medication during a surgical hospitalization between 1 January 1990 and 31 December 1999. Control patients were matched based on matching length of stay ([LOS] at least as long as time to ADE), age (within 10 years), sex, admission year, major disease category (MDC), and without an ADE. Linear regression models were used to determine the predictors of increased LOS, total hospital costs, and log-transformed total hospital costs. 60,722 patients received opioid medication during their surgical hospitalization and 2.7% experienced an opioid-related ADE. The most common clinical manifestations were nausea and vomiting (67%), and rash, hives, or itching (33.5%). No statistically significant difference was seen in mortality between ADE/non-ADE patients. ADE patients had statistically significant increases in LOS (0.53 days) and in log-transformed cost (16%). The estimated log cost difference of 16%, if applied to the median cost patient in the non-ADE group, averaged US

The Pharmacokinetics of Transdermal Fentanyl Delivered With and Without Controlled Heat

840. Opioid-related ADEs are common in hospitalized patients and increase LOS and total hospital costs.

Oral transmucosal fentanyl citrate (lollipop) premedication in human volunteers.

Preliminary reports have demonstrated that the application of local heat to the transdermal fentanyl patch significantly increased systemic delivery of fentanyl. The objective of this study was to further evaluate the pharmacokinetic effect of local heat administration on fentanyl drug delivery through the transdermal fentanyl patch delivery system in volunteers. In addition, the study was intended to document the effect of heat on steady-state transdermal fentanyl delivery. This was an open, 3-period, crossover study that evaluated the pharmacokinetics and safety of 25 microg/h transdermal fentanyl administered with and without local heat. During Sessions A and B, subjects received transdermal fentanyl for a 30-hour period. During Session A, heat was applied for 1 hour at the 24-hour time point during the 30-hour period. During Session B, heat was applied for the first 4 hours and then again for 1 hour at the 24-hour time point during the 30-hour period. The order of Sessions A and B was randomized, and a minimum of 2 weeks separated the sessions. Five of the 10 subjects returned to participate in Session C. During Session C, subjects received transdermal fentanyl 25 microg/h for 18 hours. Heat was applied during the first 4 hours of administration and then again for 15-minute periods at the 12- and 16-hour time points. Arterial blood samples for determination of serum fentanyl concentration were collected. Maximum concentration (C(max)), time to maximum concentration (t(max)), and area under the curve (AUC) were determined for each treatment period. Sedation, vital signs, oxygen saturation, and adverse events were recorded. During a period of 36 hours, there were no significant differences in C(max), AUC, or T(max) between transdermal fentanyl delivery with no heat and heat. However, significant differences were seen during the first 4 hours, with C(max) and AUC values almost 3 times higher for the heated administrations than for the administrations without heat. With heat, the mean C(max) was 0.63 ng/mL compared with a C(max) of 0.24 ng/mL without heat (P =.007). With early heat, the mean AUC was 1.22 ng/mL. h compared with 0.42 ng/mL. h without heat (P =.003). There was no statistically significant difference between the median times to achieve peak values (T(max)) during the first 4 hours. The addition of heat at 24 hours resulted in rapid increases in serum fentanyl concentrations for both groups and higher serum fentanyl concentrations for the administration that did not receive heat previously. Applying heat for 15 minutes at the 12-hour and 16-hour time points produced a rapid but short duration increase in serum fentanyl concentrations. The results suggest controlled heat might be used to significantly shorten the time needed to reach clinically important fentanyl concentrations. Controlled heat might be useful to produce rapid increases in serum concentrations for the rapid treatment of breakthrough pain.

The Iontophoresis of Fentanyl Citrate in Humans

The authors determined whether fentanyl incorporated into a candy lollipop, oral transmucosal fentanyl citrate (OTFC), would cross mucosal tissues of the mouth in sufficient quantities during and after dissolution to produce sedation and/or analgesia. Associated respiratory and circulatory changes, side effects, and plasma concentrations of fentanyl were also measured. The evaluations were done in 28 adult volunteers who received fentanyl citrate in doses of 5, 4, 2, 1, and 0.5 mg in OTFC and rapidly sucked the lollipops (N = 20) or allowed them to passively dissolve (N = 8). Rapid consumption of OTFC resulted in more rapid onset of a pleasant feeling (first subjective sensation) but not more rapid onset of objective sedation or analgesia than passive dissolution. There was a significant correlation between dose of OTFC and magnitude of sedation (P < 0.001, Spearman rank correlation = −0.82). Higher doses of OTFC produced greater and longer lasting analgesia and respiratory depression and a higher incidence of nausea and vomiting than lower doses, but pruritus (33%-87%) was not related to the dose of OTFC. Heart rate and arterial blood pressures were not changed by any dose of OTFC. The data indicate that low doses of OTFC (0.5 and 1 mg, equivalent to 5–20 äg·kgminus;1 of fentanyl citrate) produce analgesia and sedation with minimal side effects and little respiratory depression in adult volunteers and deserve further evaluation in patients.

Respiratory-Related Critical Events with Intravenous Patient-Controlled Analgesia

Background Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge‐dose relation in the delivery of fentanyl by iontophoresis. Methods Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA *symbol* min), iontophoresis 1.0 mA for 2 h (120 mA *symbol* min), and iontophoresis 2.0 mA for 2 h (240 mA *symbol* min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay. Results No fentanyl was detected after passive (0.0‐mA) fentanyl delivery. The following results were obtained for the 1.0 and 2.0‐mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 199 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng *symbol* ml sup ‐ 1 *symbol* min (P = 0.003); and mean elimination half‐lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid‐related effects occurred frequently in the 1.0‐ and 2.0‐mA administration groups. Conclusions Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge‐ dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.

Management of nonobstetric pain during pregnancy and lactation.

OBJECTIVE The objective of this study was to identify the underlying causes of respiratory-related critical events associated with intravenous patient-controlled analgesia (i.v. PCA). DESIGN The design is an observation study of prospectively collected data. SETTING An Acute Pain Service (APS) was established for the management of all patients receiving i.v. PCA therapy for pain management. As part of ongoing care, all respiratory-related critical events were documented and analyzed by staff members of the APS team. PATIENTS All patients receiving i.v. PCA therapy through the APS during the period of May 1990 through October 1992 were enrolled in the study. INTERVENTIONS Evaluation of all respiratory-related critical events was attempted to identify the underlying cause of the event and to determine if measures could be taken to prevent recurrence of similar events. OUTCOME MEASURES Any clinical event that could have or did lead to adverse patient outcome was used as an outcome measure. RESULTS A total of 3,785 patients received PCA therapy for a total of 11,521 patient care days. Fourteen critical events occurred, of which four led to increased patient care. There were eight programming errors (all involving misprogramming of the continuous infusion): three involved a family member activating the device, three were the result of an error in clinical judgment, and one involved a patient tampering with the device (one event involved more than one error). Of the four events that led to increased patient care, two involved a family member activating the device, one was the result of a programming error, and one was the result of an error in clinical judgment. All patients who experienced a critical event had an uneventful recovery. CONCLUSIONS Following review of the critical events, it was determined that the design of the PCA device contributed to the misprogramming errors and the device was removed from service. Changes in the training of physicians and nurses were instituted to avoid recurrence of other errors identified. The incidence of serious respiratory-related critical events was 0.1%. i.v. PCA therapy has the risk of potentially serious complications and requires constant physician and nursing care with an active quality assurance program.

Burn Pain: The Management of Procedure-Related Pain

P ain management practitioners assist with the treatment of pain in a variety of settings. Despite the common occurrence of pain during pregnancy, major textbooks in both pain management and obstetrics lack any concentrated discussion of the topic. In this review, we discuss the potential for fetal toxicity or teratogenic effects of medications often used to treat pain syndromes, as well as the safety of these medications in the breast-feeding mother. We then present an approach to the diagnosis and treatment of several pain management challenges that may present during pregnancy.