Fentanyl is a mu-receptor stimulating opioid first synthesized in 1960.¹ As a highly lipophilic molecule, it has significantly greater potency as compared to morphine and a much faster onset of action.¹ Fentanyl has become increasingly common through an abundance of analogs, wherein small modifications to the core fentanyl structure (4-anilidopiperidine) can lead to much more potent forms1. Several of these forms (carfentanil and lofentanil) have been developed through modification to the central piperidine ring.¹ These slight structural changes do not alter the primary mode of binding by fentanyl to the mu-opioid receptor. By binding to the mu-opioid-receptor, fentanyl can inhibit cAMP accumulation.² Desensitization further occurs through decoupling of the mu receptors from adenylyl cyclase². Fentanyl induces mu-opioid-receptor interactions with beta-arrestin, receptor phosphorylation, and ultimately allows for internationalization of the receptor for desensitization.3 Beyond beta-arrestin, fentanyl also impacts the ERK1/2 pathway through beta-arrestin activity.² Furthermore, molecular dynamics modeling of fentanyl activity in the mu-opioid receptor crystalline structure (both in its active and inactive form) has demonstrated that fentanyl converges to a singular binding orientation dependent upon stable interactions between aspartate and tyrosine residues.⁴  

In terms of surgical applications, fentanyl was first used in neuroleptanalgesia along with butyrophenone and droperidol.⁵ As a potent analgesic agent with few adverse effects, fentanyl is commonly used with different intravenous supplements to produce a “balanced” anesthesia cocktail.⁵ When applied through an intravenous bolus, fentanyl distributes rapidly through the blood plasma to reach the heart and lungs.⁵ Fentanyl also has extensive abilities to diffuse through the blood brain barrier.¹ After elimination from the vascular tissue, fentanyl redistributes to fat and muscle. Drug clearance from these tissues is slower than uptake, due to the highly lipophilic properties of fentanyl.⁵ In terms of modes of administration, fentanyl is commonly administered intravenously for postoperative anesthesia using a loading dose with a subsequent continuous infusion, a fixed background infusion with PCA pump, or with PCA pump alone.⁵ Furthermore, fentanyl is used to provide postoperative anesthesia for abdominal, orthopedic, spinal, thoracotomy, and cesarean section surgeries.^5,6 Fentanyl can also be used in a transdermal controlled release formula to allow for sustained blood/CSF opioid concentrations to minimize peak-trough effects.⁵ Thus, fentanyl is an appropriate candidate for management of chronic pain symptoms.⁷  

Side effects of fentanyl include nausea and vomiting (in around 30-40% of patients).⁵ Other minor side effects include confusion, depression, diarrhea, and weakness.⁸ As with other mu-opioid-receptor targeting analgesics, fentanyl also produces central nervous system actions including fatigue, sedation, bradycardia, and anesthesia in higher doses regardless of the mode of administration.¹ Chest wall rigidity has also been observed.¹ One major area of concern is respiratory depression, as respiratory signs should be closely monitored during and following initiation of anesthesia as well as after a dose increase.^1,5,8  

Beyond the side effects of fentanyl, overdose and addiction is a widely growing problem that should be monitored as well.⁹ Overdose of fentanyl can lead to severe respiratory depression, apnea, and death.¹ The increase in overdoses has been attributed to patient misuse, inappropriate prescriptions, and increased illicit use/abuse.¹  

As a whole, however, fentanyl is a potent rapid-acting opioid that is used for its minimal cardiovascular effects, short acting nature, and inexpensive/easy synthesis. Globally, fentanyl is found in both operative and post-operative contexts; particularly, drug delivery systems have allowed for fentanyl to become useful as a pain management opioid. Thus, while fentanyl has some side effects and is affiliated with overdose/misuse, it remains a highly important drug in anesthesia.  

Bibliography 

1.Stanley, T. H. The Fentanyl Story. The Journal of Pain 15, 1215–1226 (2014). 

 

2.Ellis, C. R., Kruhlak, N. L., Kim, M. T., Hawkins, E. G. & Stavitskaya, L. Predicting opioid receptor binding affinity of pharmacologically unclassified designer substances using molecular docking. PLOS ONE 13, e0197734 (2018). 

 

3.Lipiński, P. et al. Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis. Molecules 24, 740 (2019). 

 

4.Lipiński, P. F. J., Jarończyk, M., Dobrowolski, J. Cz. & Sadlej, J. Molecular dynamics of fentanyl bound to μ-opioid receptor. Journal of Molecular Modeling 25, (2019). 

 

5.Peng, P. W. H., MBBS, FRCPC & Sandler, A. N., MBChB, MSc, FRCPC. A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults. Anesthesiology: The Journal of the American Society of Anesthesiologists 90, 576–599 (1999). 

 

6.D’Angelo, R., MD, Gerancher, J. C., MD, Eisenach, J. C., MD & Raphael, B. L., MD. Epidural Fentanyl Produces Labor Analgesia by a Spinal Mechanism. Anesthesiology: The Journal of the American Society of Anesthesiologists 88, 1519–1523 (1998). 

 

7.Payne, R. et al. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. Journal of Clinical Oncology 16, 1588–1593 (1998). 

 

8.Fentanyl (Rx). Medscape. https://reference.medscape.com/drug/sublimaze-fentanyl-343311 

 

9.Somerville, N. J. et al. Characteristics of Fentanyl Overdose — Massachusetts, 2014–2016. MMWR. Morbidity and Mortality Weekly Report 66, 382–386 (2017). 

 

Xenon is a nonflammable, colorless, odorless noble gas that has a variety of practical applications.¹ Most commonly, xenon is used in specialized light sources, such as electronic flash bulbs for photography, ruby lasers, sunbed lamps and bactericidal lamps for food preparation and processing.¹ Xenon is also present in the atmosphere, along with nitrogen, oxygen and trace gases, and can be found in some mineral springs or even the earth’s core.² Xenon was first discovered in 1898 by the Scottish chemist William Ramsay and the English chemist Morris Travers, after distillation of krypton and isolation of the heavier gas.¹ It was previously thought to be inert, but researchers in the 20^th and 21^st centuries have shown that it is capable of reacting and forming more than one hundred new compounds.¹ Recent studies have a newfound interest in xenon as an anesthetic.³ Because the clinical application of xenon is relatively new, anesthesia providers should have thorough knowledge of its biological mechanisms, surgical applications and side effects.

Action on neurotransmitters and their receptors is responsible for xenon’s anesthetic effect.⁴ Specifically, xenon is a potent, noncompetitive inhibitor of N‐methyl‐D‐aspartate (NMDA) receptors.⁴ Studies have also found that xenon can inhibit nicotinic acetylcholine receptors (nAChRs)⁵ or even specific serotonin receptors,⁶ though the latter has never been shown in humans.⁴ Some recent researchers have found that xenon activates particular potassium channels, which may contribute to its anesthetic actions.³ Xenon does not have an effect on gamma aminobutyric acid (GABA) receptors or non-NMDA glutamatergic receptors, such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.⁴ Lack of action at GABA_A receptors is a common feature of xenon, nitrous oxide, cyclopropane and ketamine, while other inhaled anesthetics target these GABA_A receptors.³ Given all its actions in the nervous system, antagonism of the NMDA receptor is thought to be xenon’s primary site for anesthetic action.³

Xenon has advantages over many other general anesthetics in the surgical setting. For one, it provides relatively more stable intraoperative blood pressure, lower heart rate and faster emergence from anesthesia than volatile and propofol anesthesia.⁷ The hemodynamic stability of xenon makes it preferable for patients who have limited cardiovascular capabilities.⁸ Additionally, xenon is associated with the highest regional blood flow to the brain, liver, kidneys and intestines when compared to other inhaled anesthetics.⁸ Xenon is also associated with improved respiratory gas exchange when compared to sevoflurane, particularly in obese patients.⁹ Unlike other inhalational anesthetic drugs, xenon does not trigger malignant hyperthermia, has low potential for toxicity and has no teratogenic (i.e., fetus-harming) effects.⁴ In fact, xenon may even have neuroprotective effects¹⁰ that include protecting neural cells against ischemic injury from low blood flow.⁸ Furthermore, xenon exhibits more potent analgesic effects than nitrous oxide, which is the only other inhaled anesthetic with true analgesic efficacy.⁴ Its low solubility also allows for a quick induction and recovery period from anesthesia.¹¹ The use of xenon as a general anesthetic may reduce pain, improve hemodynamic stability and lower risk of organ injury when compared to other anesthetic drugs.

Unlike other inhaled anesthetics, xenon has virtually no side effects.¹² This is likely due to its extremely low chemical reactivity, which contrasts with other anesthetics that have complex molecular structures.¹² However, some researchers have found that xenon increases postoperative nausea and vomiting (PONV) compared to other general anesthetics. These findings were consistent in separate studies by Fahlenkamp et al.¹³ and Abramo et al.,⁹ as well as in a meta-analysis by Law et al.⁷ As Sanders et al. suggest, this increase in PONV may be associated with xenon’s action at serotonin receptors.⁴ However, more research is needed to clarify the cause of this unpleasant side effect.

Xenon, which has historically been used in specialized lights, is now being considered as a safe and efficacious anesthetic drug. Xenon acts on various neural receptors to cause anesthesia, and it is associated with better hemodynamic stability, lower toxicity and more potent analgesia than other anesthetics. The major disadvantage of xenon is an increase in PONV. Future research should focus on reducing the incidence of PONV; lowering costs,¹¹ which may involve changing priming and flushing practices;¹⁴ and evaluating the environmental impact of xenon when compared to greenhouse gases like nitrous oxide.⁴

1. Royal Society of Chemistry. Xenon. Periodic Table 2020; https://www.rsc.org/periodic-table/element/54/xenon.
2. Avice G, Marty B, Burgess R, et al. Evolution of atmospheric xenon and other noble gases inferred from Archean to Paleoproterozoic rocks. Geochimica et Cosmochimica Acta. 2018;232:82–100.
3. Sanders RD, Ma D, Maze M. Xenon: Elemental anaesthesia in clinical practice. British Medical Bulletin. 2005;71(1):115–135.
4. Sanders RD, Franks NP, Maze M. Xenon: No stranger to anaesthesia. BJA: British Journal of Anaesthesia. 2003;91(5):709–717.
5. Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology. 2000;93(4):1095–1101.
6. Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes. Anesthesiology. 2002;96(3):699–704.
7. Law LS, Lo EA, Gan TJ. Xenon Anesthesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Anesthesia & Analgesia. 2016;122(3):678–697.
8. Hecker K, Baumert JH, Horn N, Rossaint R. Xenon, a modern anaesthesia gas. Minerva Anestesiologica. 2004;70(5):255–260.
9. Abramo A, Di Salvo C, Foltran F, Forfori F, Anselmino M, Giunta F. Xenon anesthesia improves respiratory gas exchanges in morbidly obese patients. Journal of Obesity. 2010;2010:421593.
10. Neice AE, Zornow MH. Xenon anesthesia for all, or only a select few? Anaesthesia. 2016;71(11):1267–1272.
11. Lynch C, Baum J, Tenbrinck R, Weiskopf RB. Xenon Anesthesia. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2000;92(3):865–870.
12. LaBella F. Science lesson: How anesthetics work, and why xenon’s perfect. The Conversation. Web: The Conversation US, Inc.; September 10, 2017.
13. Fahlenkamp AV, Stoppe C, Cremer J, et al. Nausea and Vomiting following Balanced Xenon Anesthesia Compared to Sevoflurane: A Post-Hoc Explorative Analysis of a Randomized Controlled Trial. PLoS One. 2016;11(4):e0153807.
14. Nakata Y, Goto T, Niimi Y, Morita S. Cost analysis of xenon anesthesia: A comparison with nitrous oxide-isoflurane and nitrous oxide-sevoflurane anesthesia. Journal of Clinical Anesthesia. 1999;11(6):477–481.

With advances in healthcare, aging of the general population, and improvement in life expectancy, the prevalence of heart failure continues to rise, ensuring that all anesthesiologists can expect to care for patients with left ventricular assistive devices (LVAD). Thus, clinicians must understand the development and design of these devices as well as current guidelines regarding perioperative management.  While heart transplantation serves as the definitive treatment of refractory end stage heart failure, time to transplantation can be quite variable and often incorporates a temporizing measure such as an LVAD, in what is known as “bridge to therapy.” While waiting for a compatible organ, these patients often need noncardiac surgery to treat co-morbidities or injuries sustained in the interim. Select patients may also be treated permanently with an LVAD if they are considered poor candidates for transplantation. This approach to LVAD management is known as “destination therapy.” Studies report anywhere from 4% to one-half of all patients with a device will require noncardiac surgery while the LVAD is in place.¹

Prior to 2010, a significant proportion of the devices in use were “pulsatile-flow” type devices, however since that time, the majority of devices distributed have been designed for “continuous flow.” Newer designs are incorporating methods to recreate pulsatility in the peripheral vasculature that is lost with LVAD implantation. The current iterations in production are the HeartMate II and HeartWare (HVAD). The HVAD is not currently approved for destination therapy, thus the majority of devices in use are HeartMate II. Both devices operate using a magnetic field which rotates an impeller to drive blood flow through a vascular graft to the aorta. While there are significant differences in their design, both devices are common in that they are: implanted in the apex of the LV, assist cardiac output via continuous flow through ascending aorta, powered via a driveline that connects percutaneously to AC or DC power supply and the VAD controller. Flow is set at the controller and is commonly displayed in revolutions per minute (RPM). In real-time, flow through the device is dependent on preload, afterload, and actual RPM (which may differ from set RPM at the controller based on acute changes in physiology). LVADs are preload-dependent, meaning any increase in preload will be reflected as increased flow. Physiologic changes such as hypovolemia, RV failure, cardiac tamponade, or pulmonary hypertension will significantly impact preload, limiting flow through the VAD. If preload falls too low, the device may actually cause collapse of the ventricle, leading to arrythmia or hemodynamic compromise by creating a “suction” effect on the left ventricle. Changes in afterload also affect the LVAD similarly to the native heart. Decreased afterload will allow for increased flow, however in the setting of heart failure, end organs become ischemic if mean arterial pressure remains low. Therefore, a MAP between 70-90 mmHg provides optimal balance between forward flow through the VAD and end-organ perfusion. Flow is also dependent on the speed of the VAD; however, increasing the speed can also lead to emptying of the LV and overload of the aortic root, which may complicate native pulsatile flow across the aortic valve. In such a situation, all flow preferentially proceeds through the VAD into the aorta via the graft, while the aortic valve remains closed throughout the cardiac cycle. This can overload the systemic side of the valve, and has been associated with the development of aortic insufficiency, valve thrombosis, and the formation of arteriovenous malformations which have been known to cause gastrointestinal bleeding in this patient population – especially in the setting of chronic anticoagulation required for proper functioning of the device.

Given the high risk of pump thrombosis while the LVAD is in place, anticoagulation is essential. However, regimens may differ between institutions. Patients are commonly maintained on warfarin and an anti-platelet agent and bridged to heparin perioperatively – albeit, this is case and situation dependent. The reported incidence of thrombosis requiring pump exchange is around 2-12%. Modifiable risk factors for pump thrombosis are active infection and pump speed less than 8600 RPM.⁸ In the setting of a continuous flow VAD, bleeding has been reported more frequently than thrombosis, again with GI bleeding accounting for more than half of these events. Given the association of arteriovenous malformation and GI bleeding seen commonly in VAD patients, they are frequently anesthetized in the endoscopy suite to evaluate their GI lesions. LVAD patients also appear to develop an acquired type 2A Von Willebrand’s disease related to the high shear stress the VAD generates at the cellular/molecular level, resulting in loss of the high molecular weight multimers (HWMWs) responsible for binding and hemostasis. While this coagulopathy is seen in all VAD patients and resolves quickly following device removal, not all patients will have hemorrhagic complications.

Regarding the perioperative management of patients with an LVAD, there are several important considerations at each phase. Location is of concern, as a center with a heart transplant program is likely to have staff who are familiar with LVADs. Additionally, they will have a cardiothoracic surgeon and perfusionist on call in case of an emergency or complication with the device. Staffing of cases by non-cardiac anesthesiologists occurs more than 40% of the time³, again emphasizing a need for LVAD training and continuous education for all anesthesia staff. In major cases with high risk patients, or those maintained on vasoactive infusions, it is ideal for a cardiac anesthesiologist to be assigned to the case. The most commonly scheduled procedures for patients with an LVAD are tracheostomies, upper/lower endoscopies, and vascular access cases; however, it is not uncommon for these patients to present for major noncardiac surgeries.⁹ Procedural room size and design also deserves consideration, as the LVAD controller and drivelines must have ample space and cannot be blocked or under tension. Ideally, the pump will be connected to AC power for the duration of the procedure, in order to preserve battery life in case of intraoperative power failure. Batteries should remain readily available to the anesthesia provider.

Preoperatively, the patient’s anticoagulation regimen should be verified and discussed with the surgeon and cardiologist if possible. Risk of perioperative hemorrhage should be balanced with that of pump thrombosis and any other comorbidities requiring anticoagulation – such as atrial fibrillation or venous thromboembolism. No clear standard exists regarding perioperative anticoagulation in these cases; that said, according to the International Society of Heart and Lung Transplantation, warfarin and anti-platelet therapy should be continued if the risk of procedural bleeding is low in elective cases. If warfarin must be held, heparin bridging should be considered as it has been shown to decrease the incidence of pump thrombosis.⁸ In some institutions, therapy is held without bridging, especially in high risk cases such as neurosurgery or ophthalmic procedures. Yet, the risks of this must be discussed thoroughly with the multidisciplinary team caring for the patient. For emergency procedures, reversal of anticoagulation may be considered, but again must take into account the type/nature of surgery, patient comorbidities, risk factors for procedural hemorrhage versus pump thrombosis, and risk of thrombosis at other sites.

The patient’s right ventricular (RV) function should also be assessed preoperatively in the case of elective surgery. Pertinent echocardiographic studies as well as a thorough history and chart review are necessary at minimum to assess for any prior inotropic support or intervention to treat RV failure. Pre-existing RV dysfunction heralds an increased risk of intraoperative RV complications. In general, RV dilation is a sign that the cardiac circuit is more susceptible to volume overload and under-resuscitation, both of which may lead to intraoperative pump dysfunction and hypoperfusion. Preoperative RV assessment is essential in the setting of planned high-risk surgery where blood loss is expected to be significant, as it may guide the anesthesiologist in planning for invasive monitoring and/or central access. Balancing resuscitative efforts for optimal perfusion may require intraoperative transesophageal echocardiography or central pressure and cardiac output monitoring to differentiate between hypovolemia and RV dysfunction as possible causes of low preload.

Managing the patient with an LVAD intraoperatively requires an understanding of the changes in cardiac physiology seen in advanced heart failure, physiology of the LVAD circuit, and VAD monitoring parameters, as well as their clinical significance. Noninvasive blood pressures and pulse oximetry may be difficult to obtain depending on the degree of pulsatility present in the peripheral vasculature. One study reports success with a blood pressure cuff in around 50% of cases, with only a mean arterial pressure being displayed in 40% of those cases.⁴ The narrow pulse pressure physiology makes invasive monitoring with an arterial catheter useful if not necessary in many cases but also makes placement more challenging. Cerebral oximetry is also useful in select cases as a surrogate marker of cardiac output. Considerations to bear in mind when deciding whether to use invasive monitoring include the likelihood of needing multiple future surgeries, intraoperative access to extremities, and difficulty of cannulation intraoperatively in the setting of low pulsatility. If the case is relatively low risk and noninvasive monitoring is possible, it may be prudent to forego placing arterial lines as this may complicate future attempts for more high-risk surgeries.

Monitoring during procedures requires an understanding of the LVAD monitor and the impact various anesthetic interventions will have on device parameters. Power, RPM, pulsatility index, and flow are displayed on the LVAD monitor; however, flow is actually a calculated parameter and cannot be used as a direct surrogate for cardiac output for a number of reasons. The power used by the device is generally proportional to RPM and flow. Yet, there are situations such as pump thrombosis where increasing power may be a sign of poor flow. Pulsatility or the pulsatility index, is trended over the course of most major cases, as loss of pulsatility or an index less than 3 can be a sign of poor pump function. Pulsatility index (PI) is calculated as [10x(Max Flow – Min Flow)/Average Flow] and normally ranges between 3 and 6. Drops in preload and/or afterload are often reflected on the monitor as loss of pulsatility, especially when RPM is stable. Of note, PI will decrease in the setting of increasing power or RPM because the difference in maximum and minimum flow decreases. In general, lower PI is consistent with increased support from the VAD, and in the absence of changes to RPM also correlates with hypotensive episodes.

Intraoperative goals for the LVAD patient are aimed at maintaining preload and afterload and preventing right ventricular strain. Mean arterial pressure should be kept between 70-90 mmHg, as previously stated, for optimal hemodynamics , end-organ perfusion, and VAD performance. Baseline pulsatility should be noted and thereafter PI should be maintained >3. Any drops in pulsatility should be correlated with medical/surgical events and addressed quickly, with the understanding that precipitous drops will also lead to noninvasive monitor malfunction. Measures should be taken to avoid increases in pulmonary vascular resistance which will affect preload and pulsatility. Euvolemia, normoxia, normocarbia, normothermia, adequate analgesia and anxiolysis, and spontaneous ventilation are all effective in controlling RV strain. When positive pressure ventilation is required, lung protective tidal volumes and low PEEP should be used. In patients with pre-existing RV dysfunction, transesophageal echocardiography is useful intraoperatively to evaluate changes in pulsatility that accompany increased CVP. However, de novo RV dysfunction is rarely reported intraoperatively.⁹ At any rate, hemodynamic support with inotropes, vasopressors, or pulmonary vasodilators should be readily available should hemodynamic support be required intraoperatively, especially in the rare event of pump failure.

Regarding potential complications, failure of the device has been reported in 0.1% of cases, however the anesthesiologist should always be mentally prepared and equipped for this possibility. Of note, a clinically significant aortic insufficiency typically accompanies pump failure due to the altered aortic anatomy present in LVAD. Without a functioning VAD, cardiac output through the aortic valve backflows down the graft into the apex of the left ventricle and may be as high as 1-2 L/min.  Arrythmias, when sustained, are be poorly tolerated by the patient with an LVAD. Attention should be turned to electrolytes as well as the possibility of a “suctioning” event precipitated by low preload or afterload.⁹ Finally, should advanced cardiovascular life support be required, there is concern that chest compressions may damage or dislodge the LVAD; however, the American Heart Association currently recommends proceeding with chest compressions for the VAD patient in circulatory failure.¹¹

In summary, end stage heart failure and left ventricular assist devices have become more prevalent, requiring all anesthesiologists to become familiar with the perioperative management of these patients. Thorough preoperative assessment and planning is essential, as these patients live within a fairly narrow physiologic window. Risk assessment and perioperative anticoagulation planning is always necessary to balance the goals of pump thrombosis prevention and surgical hemostasis. In addition, monitoring these patients is often challenging due to the lack of pulsatile blood flow. However, meticulous preload and afterload management are essential to prevent decompensation. While there are several important considerations for the anesthesiologist, reported complications are rare and LVAD design continues to be improved upon, ensuring anesthesia providers will be challenged with caring for patients with an ventricular assist device.

References

1. Ahmed M, Le H, Aranda JM, Klodell CT. Elective noncardiac surgery in patients with left ventricular assist devices. J Card Surg. 2012;27(5):639-642. Accessed Jan 8, 2020. doi: 10.1111/j.1540-8191.2012.01515.x.
2. Arnaoutakis GJ, Bittle GJ, Allen JG, et al. General and acute care surgical procedures in patients with left ventricular assist devices. World J Surg. 2014;38(4):765-773. Accessed Dec 16, 2019. doi: 10.1007/s00268-013-2403-0.
3. Barbara DW, Wetzel DR, Pulido JN, et al. The perioperative management of patients with left ventricular assist devices undergoing noncardiac surgery. Mayo Clin Proc. 2013;88(7):674-682. Accessed Jan 8, 2020. doi: 10.1016/j.mayocp.2013.03.019.
4. Bennett MK, Roberts CA, Dordunoo D, Shah A, Russell SD. Ideal methodology to assess systemic blood pressure in patients with continuous-flow left ventricular assist devices. J Heart Lung Transplant. 2010;29(5):593-594. Accessed Jan 10, 2020. doi: 10.1016/j.healun.2009.11.604.
5. Chung M. Perioperative management of the patient with a left ventricular assist device for noncardiac surgery. Anesthesia & Analgesia. 2018;126(6):1839. https://journals.lww.com/anesthesia-analgesia/fulltext/2018/06000/Perioperative_Management_of_the_Patient_With_a.14.aspx. Accessed Jan 8, 2020. doi: 10.1213/ANE.0000000000002669.
6. Dalia AA, Cronin B, Stone ME, et al. Anesthetic management of patients with continuous-flow left ventricular assist devices undergoing noncardiac surgery: An update for anesthesiologists. Journal of Cardiothoracic and Vascular Anesthesia. 2018;32(2):1001-1012. https://www.sciencedirect.com/science/article/pii/S1053077017309205. doi: 10.1053/j.jvca.2017.11.038.
7. Kollmar JP, Colquhoun DA, Huffmyer JL. Anesthetic challenges for posterior spine surgery in a patient with left ventricular assist device: A case report. A&A Practice. 2017;9(3):77. https://journals.lww.com/aacr/fulltext/2017/08010/Anesthetic_Challenges_for_Posterior_Spine_Surgery.4.aspx. Accessed Dec 14, 2019. doi: 10.1213/XAA.0000000000000531.
8. Maltais S, Kilic A, Nathan S, et al. PREVENtion of HeartMate II pump thrombosis through clinical management: The PREVENT multi-center study. J Heart Lung Transplant. 2017;36(1):1-12. Accessed Jan 10, 2020. doi: 10.1016/j.healun.2016.10.001.
9. Mathis MR, Sathishkumar S, Kheterpal S, et al. Complications, risk factors, and staffing patterns for noncardiac surgery in patients with left ventricular assist devices. Anesthesiology. 2017;126(3):450-460. Accessed Jan 10, 2020. doi: 10.1097/ALN.0000000000001488.
10. Nelson EW, DO, Heinke T, MD, Finley A, MD, et al. Management of LVAD patients for noncardiac surgery: A single-institution study. Journal of Cardiothoracic and Vascular Anesthesia. 2015;29(4):898-900. https://www.clinicalkey.es/playcontent/1-s2.0-S1053077015000506. doi: 10.1053/j.jvca.2015.01.027.
11. Peberdy MA, Gluck JA, Ornato JP, et al. Cardiopulmonary resuscitation in adults and children with mechanical circulatory support: A scientific statement from the american heart association. Circulation. 2017;135(24):e1115-e1134. Accessed Jan 10, 2020. doi: 10.1161/CIR.0000000000000504.
12. Uriel N, Han J, Morrison KA, et al. Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: A multifactorial phenomenon. J Heart Lung Transplant. 2014;33(1):51-59. Accessed Jan 8, 2020. doi: 10.1016/j.healun.2013.10.005.

Butorphanol is a synthetic opioid drug that is used for analgesia, often as an adjunct to other anesthetic drugs.¹ Butorphanol is a derivative of morphinan that was developed in the 1970s for use as an analgesic and for antagonism of narcotic drugs,² and is now sold under the brand name Stadol.³ Butorphanol is about four to seven times as potent as morphine.⁴ Because anesthesiology professionals often use opioids, they should have thorough knowledge of butorphanol’s biological mechanisms, uses and perioperative implications.

Butorphanol, also known as butorphanol tartrate, has a molecular formula of C₂₁H₂₉NO₂.³ Though the exact mechanisms of its action are unknown, it is believed to interact with opioid receptors in the central nervous system.¹ Butorphanol is a partial m-opioid receptor antagonist and k-opioid receptor agonist,⁵ and may even have agonistic effects at the σ-opioid receptor.¹ Its antagonism of the m-opioid receptor may result from competitive inhibition or could be due to other mechanisms.¹ According to research, butorphanol is equally as analgesic as another opioid agonist-antagonist nalbuphine.⁶ Butorphanol binds to serum proteins at approximately 80 percent, which is a lower rate than drugs like buprenorphine but higher than many other opioids.¹ Its protein-binding rate affects its elimination half-life of 18 hours; higher protein binding leads to slower elimination.¹ Butorphanol is extensively metabolized in the liver, and while its metabolites have not been studied in humans, they show some analgesic properties in animals.¹ Because of the liver’s role in its metabolism, butorphanol’s elimination—which occurs by excretion through urine and feces—is slowed by hepatic impairment.¹ In general, butorphanol is more potent than morphine and has a shorter duration of action with minimal sedation.⁷

The uses of butorphanol vary widely, ranging from producing analgesia in veterinary medicine to serving as an antitussive (anti-cough) medication in humans.⁸ It provides poor-to-moderate pain relief that is better for visceral (i.e., organ) pain than somatic (i.e., skin, muscles and soft tissue) pain.⁸ Though it was first launched as a parenteral formulation, it can now be used in intranasal form for noninvasive analgesia for moderate to severe pain.¹ When administered parenterally, butorphanol serves as a narcotic analgesic on its own or as an adjunct to general anesthesia.⁹ As a nasal spray, it is most often used for treatment of migraine headaches.⁹

Several researchers have approached the uses of butorphanol during the perioperative period. An older study by Bowdle et al. found that intravenous butorphanol improved ventilation after fentanyl anesthesia.¹⁰ Laffey and Kay’s study found that butorphanol premedication was as effective as morphine in reducing pain during abdominal hysterectomy, with the advantage of fewer side effects.¹¹ Meanwhile, Vogelsang and Hayes’ review recognizes the uses of butorphanol as a preoperative sedative and analgesic, a supplement to balanced anesthesia, an obstetric analgesic and a suppressant of post-anesthesia shaking and post-labor pain.¹² Its receptor specificity limits respiratory depression, gastrointestinal side effects and risk of dependency when compared to morphine and meperidine.¹² Other studies have found that compared to other opioids, butorphanol is associated with less cardiovascular or respiratory depression, though there is species variability.⁴ While butorphanol may have fewer adverse effects than other opioids, it may also cause undesired sedation when used as an analgesic.⁶ Additionally, it can cause confusion, euphoria, agitation, itching, sweating, abdominal bloating, nausea, vomiting and constipation, though gastrointestinal side effects may be less intense than with other opioids.⁹ More serious adverse effects—like those of other opioids—include hypoventilation, cardiovascular insufficiency, respiratory depression, coma and death.^1,9

Butorphanol is a synthetic opioid drug that is more potent than morphine, but without many of the adverse side effects. Butorphanol is usually administered parenterally or intranasally, and can be used for veterinary or human medicine for pain control, or even as an antitussive. Though butorphanol has relatively fewer side effects than other opioid drugs and is less likely to result in overdose, it can still be accompanied by sedation, euphoria, nausea, vomiting, gastrointestinal symptoms, respiratory depression, cardiovascular issues or even death. Anesthesia providers should thoroughly evaluate patients who may benefit from pain control with butorphanol.

1. Butorphanol. DrugBank February 10, 2020; https://www.drugbank.ca/drugs/DB00611.
2. Pircio AW, Gylys JA, Cavanagh RL, Buyniski JP, Bierwagen ME. The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic. Archives Internationales de Pharmacodynamie et de Therapie. 1976;220(2):231–257.
3. Butorphanol. PubChem Database. Web: National Center for Biotechnology Information; 2020.
4. Bush M, Citino SB, Lance WR. Chapter 77—The Use of Butorphanol in Anesthesia Protocols for Zoo and Wild Mammals. In: Miller RE, Fowler M, eds. Fowler’s Zoo and Wild Animal Medicine. Saint Louis: W.B. Saunders; 2012:596–603.
5. Gaertner DJ, Hallman TM, Hankenson FC, Batchelder MA. Chapter 10—Anesthesia and Analgesia for Laboratory Rodents. In: Fish RE, Brown MJ, Danneman PJ, Karas AZ, eds. Anesthesia and Analgesia in Laboratory Animals (Second Edition). San Diego: Academic Press; 2008:239–297.
6. Coté CJ, Lerman J, Ward RM, Lugo RA, Goudsouzian N. Chapter 6—Pharmacokinetics and Pharmacology of Drugs Used in Children. In: Coté CJ, Lerman J, Todres ID, eds. A Practice of Anesthesia for Infants and Children (Fourth Edition). Philadelphia: W.B. Saunders; 2009:89–146.
7. Aarnes TK, Muir WW. Chapter 26—Pain Assessment and Management. In: Peterson ME, Kutzler MA, eds. Small Animal Pediatrics. Saint Louis: W.B. Saunders; 2011:220–232.
8. Hammond R, Christie M, Nicholson A. Chapter 14—Opioid analgesics. In: Maddison JE, Page SW, Church DB, eds. Small Animal Clinical Pharmacology (Second Edition). Edinburgh: W.B. Saunders; 2008:309–329.
9. Butorphanol. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; April 29, 2019.
10. Bowdle TA, Greichen SL, Bjurstrom RL, Schoene RB. Butorphanol improves CO2 response and ventilation after fentanyl anesthesia. Anesthesia and Analgesia. 1987;66(6):517–522.
11. Laffey DA, Kay NH. Premedication with butorphanol: A comparison with morphine. British Journal of Anaesthesia. 1984;56(4):363–367.
12. Vogelsang J, Hayes SR. Butorphanol tartrate (stadol): A review. Journal of Postanesthesia Nursing. 1991;6(2):129–135.

Awake craniotomy is a procedure in which a surgeon temporarily removes a piece of skull to access the brain while the patient remains awake.¹ The advantage of an awake craniotomy is that it allows the physician to ensure that the patient’s critical functions, such as language and movement, remain intact, despite manipulation of the brain.¹ For example, the surgeon may want to evaluate a patient’s motor functions throughout surgery in order to prevent causing permanent disability.² Awake craniotomies are frequently used for extraction of brain tumors such as gliomas, which occur in the frontal and temporal lobes near areas that control speech and motor function.¹ While brain tissue is not sensitive to pain, anesthesia providers are responsible for sedation before surgery; waking up the patient during the operation; and numbing the muscles, skin and bone surrounding the surgical area.¹ Anesthesiology practitioners must be familiar with the anesthetic techniques available for awake craniotomy and the efficacy of these techniques.

Anesthesia provision for awake craniotomy is a complex endeavor. For one, such a procedure is associated with significant anxiety, and some patients may be reluctant to undergo surgery while awake.³ Thus, the anesthesiologist, surgeon and other health care professionals should establish a good relationship with the patient before surgery in order to optimize patient comfort.³ The anesthesia provider may also choose to premedicate patients who have conditions such as epilepsy or are of young age.³ However, the clinician must avoid providing medications that could impair neurocognitive function or delay the intraoperative wake-up period.³ During the procedure, the patient will require distinct anesthetic management in the pre-awake and awake stages.³ A study by Eseonu et al. found that monitored anesthesia care (MAC), using an unprotected airway, and the asleep-awake-asleep (AAA) technique, using a partially or totally protected airway, were both safe and effective.⁴ The literature show a variety of options for patient positioning,³ airway management⁵ and anesthetic or analgesic agents⁶ throughout the awake and asleep phases. According to a recent review by Sewell and Smith, there is no evidence that one anesthetic approach is better than the others, and failure of awake craniotomy is not associated with anesthetic technique.⁶ Anesthesia providers may use different strategies within and among patients depending on institution policy and patient-related factors.

Despite the widespread use of awake craniotomy, the evidence is mixed on its advantages over brain surgery under general anesthesia.³ For example, a study by Gravesteijn et al. on insular glioma surgery found no differences between awake craniotomy and craniotomy under general anesthesia in extent of resection, neurological outcomes or patient survival.⁷ Given that awake craniotomy was more challenging for patients and their caregivers after surgery, the authors suggest that awake craniotomy may not be the better solution.⁷ A different study by Eseonu et al. found that awake craniotomy had advantages over general anesthesia for perirolandic glioma resection, with more frequent total resections, better postoperative function and shorter hospitalizations.⁸ A trial by Sacko et al. showed that awake craniotomy was associated with sooner discharge than craniotomy under general anesthesia, as well as maximal removal of lesions and low neurological complication rates.⁹ Furthermore, Ohtaki et al. found that depth of anesthesia was related to motor response during awake craniotomy, with awake patients producing the most reliable measurements and allowing for best interpretation of motor function.² Though awake craniotomy may have several advantages over surgery under general anesthesia, it may not be useful for all types of tumor resections.

Anesthesiologists are faced with decisions regarding anesthetic drugs, patient positioning and sleep-wake techniques during awake craniotomy. Additionally, anesthesia providers must consider the possibility of using general anesthesia for craniotomies in specific situations. More studies are needed to establish evidence-based practices in anesthesia for awake craniotomy. Once more data are available, future policy should standardize awake craniotomy anesthetic techniques across institutions.

References

1) Raeke M. Awake craniotomy for brain tumors: 8 questions. Cancerwise April 24, 2018; https://www.mdanderson.org/publications/cancerwise/awake-craniotomy-for-brain-tumors–8-questions.h00-159223356.html.

2) Ohtaki S, Akiyama Y, Kanno A, et al. The influence of depth of anesthesia on motor evoked potential response during awake craniotomy. Journal of Neurosurgery JNS. 2017;126(1):260–265.

3) Meng L, McDonagh DL, Berger MS, Gelb AW. Anesthesia for awake craniotomy: A how-to guide for the occasional practitioner. Canadian Journal of Anesthesia/Journal canadien d’anesthésie. 2017;64(5):517–529.

4) Eseonu CI, ReFaey K, Garcia O, John A, Quiñones-Hinojosa A, Tripathi P. Awake Craniotomy Anesthesia: A Comparison of the Monitored Anesthesia Care and Asleep-Awake-Asleep Techniques. World Neurosurgery. 2017;104:679–686.

5) Sivasankar C, Schlichter RA, Baranov D, Kofke WA. Awake Craniotomy: A New Airway Approach. Anesthesia & Analgesia. 2016;122(2):509–511.

6) Sewell D, Smith M. Awake craniotomy: Anesthetic considerations based on outcome evidence. Current Opinion in Anesthesiology. 2019;32(5):546–552.

7) Gravesteijn BY, Keizer ME, Vincent AJPE, Schouten JW, Stolker RJ, Klimek M. Awake craniotomy versus craniotomy under general anesthesia for the surgical treatment of insular glioma: choices and outcomes. Neurological Research. 2018;40(2):87–96.

8) Eseonu CI, Rincon-Torroella J, ReFaey K, et al. Awake Craniotomy vs Craniotomy Under General Anesthesia for Perirolandic Gliomas: Evaluating Perioperative Complications and Extent of Resection. Neurosurgery. 2017;81(3):481–489.

9) Sacko O, Lauwers-Cances V, Brauge D, Sesay M, Brenner A, Roux F-E. Awake Craniotomy vs Surgery Under General Anesthesia for Resection of Supratentorial Lesions4. Neurosurgery. 2011;68(5):1192–1199.