Peter L. Bailey

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.

Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. Results of a Canadian double-blind, crossover, multicenter study.

We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimers disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

Postoperative tracheal extubation

A lthough tracheal intubation receives much attention, especially with regard to management of the difficult airway, tracheal extubation has received relatively little emphasis. The scope and significance of problems occurring after tracheal extubation are real. Adverse outcomes involving the respiratory system comprise the single largest class of injury reported in the ASA Closed Claims Study (1). Obvious adverse events related to tracheal extubation accounted for 35 of the 522 or 7% of the respiratoryrelated claims. Certainly additional morbidity related to extubation could be accounted for in other categories of adverse respiratory events, such as inadequate ventilation, airway obstruction, bronchospasm, and aspiration. Others have documented a 4%-9% incidence of serious adverse respiratory events in the immediate postextubation period (2,3) and preventable anesthesia-related etiologies were noted as important by Ruth et al. (2). Mathew et al. (4), in a retrospective review of more than 13,000 anesthetics, noted that emergency tracheal reintubations occurred in only 0.19% of patients, and that the majority of tracheal reintubations were due to preventable anesthesia-related factors. Perhaps a greater percentage of patients experience postextubation difficulties but do not require reintubation of the trachea. Reasons for tracheal reintubation in the intensive care setting may differ, but the reported incidence in that arena is similarly 4% (5). Anesthesiologists recognize the immediate postextubation period as one where patients are particularly vulnerable. Events such as laryngospasm, aspiration, inadequate airway patency, or inadequate ventilatory drive can occur and frequently result in hypoxemia. Such hypoxemia is most often corrected within minutes. Less frequently, postextubation hypoxemia can rapidly result in serious morbidity. In this report we will review the known physiologic and pathophysiologic changes associated with anesthesia and surgery that can influence respiratory function after tracheal

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.

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.

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.

A survey of the use of ultrasound during central venous catheterization.

BACKGROUND:Complications during central venous catheterization (CVC) are not rare and can be serious. The use of ultrasound (US) during CVC has been recommended to improve patient safety. We performed a survey to evaluate the frequency of, and factors influencing, US use. METHODS:We conducted an electronic survey of all members of the Society of Cardiovascular Anesthesiologists. Univariate and multivariate logistic regressions were used to assess the association between the frequency of US use and hospital and physician factors. All tests were two-sided, and a P value <0.05 was considered statistically significant. RESULTS:Of the 4235 members, 1494 responded (response rate = 35.3%). Two-thirds of the respondents never, or almost never, use US, whereas only 15% always, or almost always, use US. Thirty-three percent of the respondents never, or almost never, have US available, whereas 41% stated that US is always, or almost always, available. Availability of US equipment was strongly associated with US use for CVC (adj OR = 18.9; P value <0.001). The most common reason cited for not using US was “no apparent need for the use of US” (46%). When US was used, rescue or screening approaches were more common (72%) than real-time use (26%). CONCLUSIONS:The use of US during CVC remains limited and is most strongly associated with the availability of equipment. Screening and rescue use of US are more common than real-time guidance. Our survey suggests that current use of US during CVC differs from existing evidence-based recommendations.

Effects of intrathecal morphine on the ventilatory response to hypoxia.

BACKGROUND Intrathecal administration of morphine produces intense analgesia, but it depresses respiration, an effect that can be life-threatening. Whether intrathecal morphine affects the ventilatory response to hypoxia, however, is not known. METHODS We randomly assigned 30 men to receive one of three study treatments in a double-blind fashion: intravenous morphine (0.14 mg per kilogram of body weight) with intrathecal placebo; intrathecal morphine (0.3 mg) with intravenous placebo; or intravenous and intrathecal placebo. The selected doses of intravenous and intrathecal morphine produce similar degrees of analgesia. The ventilatory response to hypercapnia, the subsequent response to acute hypoxia during hypercapnic breathing (targeted end-tidal partial pressures of expired oxygen and carbon dioxide, 45 mm Hg), and the plasma levels of morphine and morphine metabolites were measured at base line (before drug administration) and 1, 2, 4, 6, 8, 10, and 12 hours after drug administration. RESULTS At base line, the mean (+/-SD) values for the ventilatory response to hypoxia (calculated as the difference between the minute ventilation during the second full minute of hypoxia and the fifth minute of hypercapnic ventilation) were similar in the three groups: 38.3+/-23.2 liters per minute in the placebo group, 33.5+/-16.4 liters per minute in the intravenous-morphine group, and 30.2+/-11.6 liters per minute in the intrathecal-morphine group (P=0.61). The overall ventilatory response to hypoxia (the area under the curve) was significantly lower after either intravenous morphine (20.2+/-10.8 liters per minute) or intrathecal morphine (14.5+/-6.4 liters per minute) than after placebo (36.8+/-19.2 liters per minute) (P=O.003). Twelve hours after treatment, the ventilatory response to hypoxia in the intrathecal-morphine group (19.9+/-8.9 liters per minute), but not in the intravenous-morphine group (30+/-15.8 liters per minute), remained significantly depressed as compared with the response in the placebo group (40.9+/-19.0 liters per minute) (P= 0.02 for intrathecal morphine vs. placebo). Plasma concentrations of morphine and morphine metabolites either were not detectable after intrathecal morphine or were much lower after intrathecal morphine than after intravenous morphine. CONCLUSIONS Depression of the ventilatory response to hypoxia after the administration of intrathecal morphine is similar in magnitude to, but longer-lasting than, that after the administration of an equianalgesic dose of intravenous morphine.

Transesophageal Echocardiography: An Objective Tool in Defining Maximum Ventricular Response to Intravenous Fluid Therapy

Ventricular preload is an important determinant of cardiac function, which is indirectly measured in the clinical setting by the pulmonary capillary wedge pressure (PCWP).Transesophageal echocardiography (TEE) is rapidly gaining acceptance as a monitor of cardiac function. Although it provides high-resolution images of cardiac structures, clinical assessment of ventricular preload using TEE has been subjective, since quantitative measurements have been difficult to perform in a timely fashion. Automated border detection (ABD) is a new technology used in conjunction with TEE that allows quantitative real-time, two-dimensional measurement of cavity areas. To determine whether end-diastolic area (EDA) measured by ABD can be used to determine an appropriate end point for intravenous fluid administration, nine mongrel dogs were studied. Anesthetized animals were hemorrhaged to achieve a central venous pressure of 0-5 mm Hg. Each animal was then given intravenous fluid (autologous blood followed by hetastarch) until a peak in thermodilution cardiac output (CO) was achieved. Measures of PCWP, EDA, CO, and left ventricular stroke work (LVSW) were obtained after each fluid bolus. Bivariate plots displaying administered volume versus CO, LVSW, and EDA revealed parallel curves for each of these variables with peaks evident at cumulative volumes of 50-55 mL/kg. Multiple regression with mixed model analysis of covariance was performed to determine the significance of EDA in relation to changes in CO and LVSW. Analysis was likewise performed comparing the relationship between PCWP and changes in CO or LVSW. A significant relationship was demonstrated when comparing EDA to changes in CO and LVSW (P = 0.03 and P < 0.0001, respectively). Similar analysis comparing PCWP to changes in CO and LVSW failed to demonstrate a significant relationship (P = 0.54 and P = 0.36, respectively). These data suggest that changes in EDA measured using TEE with ABD are related to trends in cardiac function and can suggest an appropriate end point for intravenous fluid administration as defined by maximum CO and LVSW. PCWP did not demonstrate a significant relationship to changes in CO and LVSW. (Anesth Analg 1996;83:1149-53)