Paul H. Alfille

The Common Inhalation Anesthetic Isoflurane Induces Apoptosis and Increases Amyloid β Protein Levels

Background:The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease–associated amyloid &bgr; protein (A&bgr;), the principal peptide component of cerebral &bgr;-amyloid deposits. Methods:H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and A&bgr; levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked immunosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or A&bgr; generation. Results:Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of A&bgr; in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in A&bgr; and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments. Conclusion:A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases A&bgr; production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of A&bgr; is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral A&bgr; and elderly patients at increased risk for postoperative cognitive dysfunction.

A quality improvement study of the placement and complications of double-lumen endobronchial tubes.

To assess the complications of conventional and fiberoptic endobronchial intubations using reusable (Leyland, London) and disposable (Rüsch, Waiblinger, Germany; Sheridan, Argyle, NY) double-lumen tubes (DLTs), endobronchial intubations occurring over a 12-month period were prospectively studied at this hospital. Residents working with staff anesthesiologists placed either left or right reusable (Leyland) or disposable (Rüsch or Sheridan) DLTs. The DLT used, the use of fiberoptic bronchoscopy (FOB), findings at FOB if used during the intubation or operation, and complications occurring during the case (SpO2 < 90%, peak inflation pressure > 40 cm H2O, air trapping, poor lung isolation, and airway trauma) were recorded. Two hundred thirty-four intubations were analyzed (102 right, 132 left; 70 Leyland reusable DLTs, 66 Rüsch disposable tubes, and 98 Sheridan tubes). Physical signs alone were used to confirm tube position more frequently when Leyland tubes were placed compared with disposable tubes (79% v 39%, P < 0.0001). Rüsch and Sheridan DLTs had similar rates of conventional placement. Nineteen percent of reusable tubes and 44% of disposable tubes required position adjustments using FOB during the initial intubation (P = 0.0002). Disposable tubes also more commonly required readjustment using FOB during the operation (30% v 7%, P < 0.0005). Complications occurred in 42/234 patients (18%). The frequency of specific complications was: decreased SpO2, 9%; increased airway pressures, 9%; poor lung isolation, 7%; air trapping, 2%, and airway trauma, 0.4%. Right-sided Sheridan DLTs had a statistically higher incidence of malposition, resulting in poorer lung isolation.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of esmolol and labetalol to attenuate hyperdynamic states after electroconvulsive therapy

We studied 18 patients (age range, 53-90 yr) with at least one cardiovascular risk factor who were treated with electroconvulsive therapy (ECT) and compared effects of five pretreatments: no drug; esmolol, 1.3 or 4.4 mg/kg; or labetalol, 0.13 or 0.44 mg/kg. Each patient received all five treatments, during a series of five ECT sessions. Pretreatment was administered as a bolus within 10 s of induction or anesthesia. Doses of methohexital and succinylcholine were constant for the series of treatments and the assignment to no drug or to drug and dose was determined by randomized block design. Measurements of systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) were recorded during the awake state and 1, 3, 5, and 10 min after the seizure. The deviation of ST segments from baseline was measured by an electrocardiogram (ECG) monitor equipped with ST-segment analysis software. The results (mean +/- SEM) show that without pretreatment, there were significant (P<0.05) peak increases in SBP and HR (55 +/- 5 mm Hg and 37 +/- 6 bpm, respectively), recorded 1 min after the seizure. Comparable reductions (by approximately 50%) in these peak values were achieved after esmolol (1.3 mg/kg) or labetalol (0.13 mg/kg), and cardiovascular responses were nearly eliminated after the same drugs in doses of 4.4 and 0.44 mg/kg, respectively. The deviation of ST-segment values from baseline in any lead was not measurably influenced by either antihypertensive drug. SBP values were lower after labetalol 10 min after the seizure, but not after esmolol. Asystolic time after the seizure was not significantly longer with either drug. No adverse reactions were observed. Because SBP effects were still present 10 min after the seizure, esmolol may be preferred if administration of a large dose of a beta-adrenergic blocker is contemplated. (Anesth Analg 1995;80:557-61)

Airway obstruction following application of cricoid pressure

The widely practiced rapid-sequence induction with application of cricoid pressure is designed to facilitate endotracheal intubation in patients considered to be at high risk of aspiration. We describe a case in which this maneuver was performed on a patient with an undiagnosed traumatic injury to the larynx. The resulting airway obstruction required emergency surgical intervention. The clinical presentation, diagnosis, and management of such injuries are discussed.

Comparison of thoracic and lumbar epidural infusions of bupivacaine and fentanyl for post-thoracotomy analgesia.

Epidural analgesia, via either a thoracic or lumbar route, is commonly used to provide postoperative analgesia following thoracotomy for pulmonary resection, but little data indicate which location is better in terms of postoperative analgesia, side effects, or associated complications. In this study, 45 patients, who were scheduled to have epidural analgesia and undergo a lateral thoracotomy, were randomized to receive either a thoracic or a lumbar catheter. Pain assessments and routine clinical data were recorded to determine if either thoracic or lumbar epidural catheters provided superior analgesia, fewer side effects, or fewer complications. This study found no statistical difference in pain relief or side effects between lumbar and thoracic epidural analgesia for post-thoracotomy pain. An increased infusion rate (6.4 +/- 1.9 v 5.1 +/- 1.4 mL/h, P = 0.02) was required in the lumbar group to achieve equivalent analgesic levels.

Control of perioperative muscle strength during ambulatory surgery.

Purpose of review This review describes strategies to control perioperative muscle strength in patients undergoing ambulatory surgery. Recent findings Although it is impossible to improve muscle relaxation (defined as absence of electrical activity) of intact resting muscle by hypnotics, analgesia is required to prevent pain-evoked muscular contractions during surgery. Regional anesthesia, as well as hypnotics and opioids, promotes intraoperative muscle relaxation. Neuromuscular blocking agents (NMBAs) induce dose-dependent muscle relaxation, but their effects vary widely between individuals, and postoperative residual curarization (PORC) exposes patients to additional risk. Low doses of NMBAs should, therefore, be used, effects be monitored quantitatively by acceleromyography, and residual neuromuscular block be reversed. Acetylcholinesterase inhibitor reversal can cause respiratory side effects, so the lowest efficacious dose should be used: as little as 0.015–0.025 mg kg−1 of neostigmine is required at a train-of-four count of four with minimal fade. Sugammadex encapsulates steroidal NMBAs. Sugammadex reversal is a viable approach to rapidly antagonize deep levels of neuromuscular block. Summary Optimal muscle relaxation for ambulatory surgery results from a judicious combination of regional anesthesia, opioids, and low doses of NMBAs. The effects of NMBAs should be monitored quantitatively by acceleromyography and reversed appropriately.

Anesthesia for tracheal resection and reconstruction.

Tracheal resection and reconstruction (TRR) is the treatment of choice for most patients with tracheal stenosis or tracheal tumors. Anesthesia for TRR offers distinct challenges, especially for the less experienced practitioner. This article explores the preoperative assessment, strategies for induction and emergence from anesthesia, the essential coordination between the surgical and anesthesia teams during airway excision and anastomosis, and postoperative care. The most common complications are reviewed. Targeted readership is practitioners with less extensive experience in managing airway surgery cases. As such, the article focuses first on the most common proximal tracheal resection. Final sections discuss specific considerations for more complicated cases.

Robots with a Social Memory

More than occasionally we hear the protest that “People are not robots!” when trying to bring consistency to medical practice. We certainly agree, although the era of absolute clinical autonomy in medicine is long over. Ledolter et al. are likely in for a round of “not robots!” protests with their contribution in this month’s issue of Anesthesia & Analgesia. People will take exception to being compared to machines that process jobs, and the implication that jobs are kept waiting because of poor decisions by the machines. Tough! The server/job analogy describes any system in which a limited, high-value resource (e.g., a physician) sequentially serves a series of clients (patients). This simple observation in no way devalues the unique role anesthesiologists play in patient care. Ledolter et al. make a simple observation: at night, when 3 operating rooms are allotted to be available, the on-call anesthesiology team frequently runs only 2 rooms, delaying service for patients, surgeons, and the rest of the hospital system. Several important questions arise. Is waiting a function of which anesthesiologist is on-call and making the choices about activating the second-call anesthesiologist, or are all alike in their decisions to let everyone else wait? Does the amount of waiting change over time? Do policy changes or implementation of organizational structure influence performance? These are important issues for hospital and anesthesia practice leadership. Ledolter et al. demonstrate that a simple method for doing so is as good as more complex techniques. Statistical Process Control (SPC) methodologies provide powerful, useful tools for monitoring waiting as a function of time (i.e., to answer the question, “Is my system performance changing or is it the same over time?). Despite the intimidating name, SPC methodologies need not be intimidating. Ledolter et al. demonstrate that a simple SPC technique developed by Shewhart, meant to be implemented with pencil and paper, is just as good as more sophisticated, less accessible methods. This conclusion that simple methods will serve is refreshing. The going gets heavier when trying to decide whether all anesthesiologists are alike in their decision making. Here, it is important to know whether all of the anesthesiologists (or more specifically, their observed behaviors) come from the same population, or whether some of the anesthesiologists are different from the others. Picking the correct distribution with which to model the population of anesthesiologist decisions is the critical step. Here, Ledolter et al. opt for the negative binomial distribution. What is it, and why use it? The negative binomial distribution accurately describes the probability, in successive tosses of a fair coin, of getting 1, 2, 3, ..., n heads (or tails) in a row, or of having a third case waiting to start once 2 cases are already under way. Through hypothesis testing with reference to the negative binomial distribution, Ledolter et al. conclude that all anesthesiologists are the same. They (or “we”) make poor resource utilization decisions, letting a third case wait (including patients, surgeons, nurses, and staff) instead of calling in the second-call anesthesiologist. Poor resource utilization is one potential lens through which the anesthesiologists’ decisions can be examined. Decisions involving calling in additional providers are inevitably influenced by more factors. The group of physicians will all share roles as the “caller” or the “one called in” over the course of time. Social psychology gives insight into how people make decisions given these constraints. Game theory, in the form of the prisoner’s dilemma, is a useful construct to explain cooperative behavior (defined as cooperation with a second “prisoner,” in this case the second anesthesiologist) and uncooperative behavior. Two prisoners are presented with a choice: “cooperate” with each other, meaning that they remain silent during interrogation, or “defect,” meaning that they “rat out” the other prisoner. They are interrogated separately, and neither knows the other’s decision. If both prisoners “cooperate” (remain silent), they receive a very modest sentence. If both prisoners “defect,” they each receive half of the maximum sentence. However, if one prisoner “cooperates” and one prisoner “defects,“ the cooperating prisoner (i.e., the one who remains silent) receives the maximum sentence, while the defector goes free. Trusting your counterpart to cooperate is risky. The logical choice is to defect, because you always do better if you defect than if you cooperate (although Douglas Hofstadter suggested that a “superrational” individual would assume that both prisoners will reach the same conclusion, *From Harvard Medical School and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital.

Using recruitment maneuvers to decrease tidal volumes during one-lung ventilation.

N O anesthesiologist has failed to be amazed at the process of reexpanding the lung after thoracotomy. A long sustained breath turns a meaty atelectatic organ into a pink and airy one, one acinar unit at a time. During thoracic surgeries, the one ventilated lung has to sustain the patient. Overcoming hypoxemia is the battle for thoracic anesthesiologists. What is the best ventilatory strategy to improve oxygenation while minimizing lung injury during one-lung ventilation (OLV)? Different strategies have been used to improve hypoxemia during OLV. Relatively high tidal volumes (10 ml/kg and greater) have been used to improve oxygenation in OLV. However, the use of these larger tidal volumes during OLV has been shown to be associated with lung injury. Alveolar recruitment maneuvers (ARM) have been well studied and are now being used in many areas of ventilatory management. The underlying concept is that by expanding atelectatic areas of lungs with ARM, the subsequent administered tidal volume and ventilation stresses are distributed more uniformly. The effects of ARM are thought to last if moderate amounts of supplemental oxygen and positive end-expiratory pressure are used. Given that background, Kozian et al. sought to compare the lung densities and lung mechanics produced in anesthetized piglets who all received ARM while the two lungs were ventilated and then received either larger or smaller tidal volumes during OLV. Therefore, all the animals received a recruitment maneuver as well as 5 cm H2O positive endexpiratory pressure, a standard inspiratory:expiratory ratio, and respiratory rates that were adjusted to achieve a specific carbon dioxide level. The ARM was followed by lower tidal volume ventilation (5 ml/kg) to one group during OLV. The second group received 10 ml/kg during OLV. Kozian et al. used spiral computed tomography scans before and after they administered an ARM on the anesthetized piglets. Oxygenation was significantly improved by the ARM, as oxygen went from 138 to 191 mmHg. There was a hemodynamic price for the ARM; there was a drop of approximately 10% in cardiac index, mean arterial pressures, and heart rates, but these changes were transient. The ARM also improved lung density distributions, compliance, and oxygenation in the animals that received the ARM before the administration of the lower tidal volumes during OLV. In contrast, the animals that received a larger tidal volume during OLV had reasonable oxygenation but an inhomogeneous distribution of densities in their ventilated lungs and increased mechanical stress in their one ventilated lung. The conclusion of the authors was that the combination of ARM and low tidal volume achieved improved oxygenation with improved tissue stretching. The ARM itself resulted in an increased fraction of normally aerated lung, and although the administration of 10 ml/kg led to further increased areas of aeration, the effect was seen only at end-inspiration because the lung density distribution was the same at end-expiration in both groups. This difference in aeration between end-inspiration and end-expiration suggests there may have been collapse and reopening in the lungs of the animals receiving the larger tidal volumes. Cyclic changes during mechanical ventilation have been associated with the release of inflammatory mediators in the lung. Now the caveats: the work by Kozian et al. needs some additional study before we will know how to apply ARM in clinical practice. The experiments were done in healthy pigs, not in humans with various lung diseases. Some models of lung injury are worsened with recruitment maneuvers. The authors performed the recruitment maneuvers only before lung isolation, which may be contraindicated in severe bullous disease, pneumothorax, or in patients with airway disruption. Although the authors cite evidence regarding lung injury caused by larger tidal volumes, they present no data regarding lung injury in this investigation. There are also no long-term outcome data in this report. Indeed, the animals were sacrificed before extubation, so there is not even data regarding recovery. Whether or not the use of lower tidal volumes during OLV after recruitment improves long-term clinical outcomes is not known. In a large study of adult respiratory distress syndrome, recruitment improved ventilation parameters but not patient outcomes. We await additional investigations to guide us during our battle to improve gas exchange and outcomes for patients requiring OLV.