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INTRODUCTION

Pharmacists' roles in surgery and anesthesiology are growing. Pharmacists have expanded their involvement in monitoring surgical stock-distribution systems, enforcing controlled-substance procedures, supplying drug information, and providing pharmaceutical care to surgical patients. One reason pharmacists are more critical in the operative theater is a growing understanding of the need for rational drug therapy in the perioperative period.

This continuing education module addresses 4 perioperative areas in which pharmacists are key resource personnel: surgical site infection prevention; recognition and treatment of malignant hyperthermia (MH); appropriate use of alvimopan (Entereg); and recognition and treatment of local anesthetic systemic toxicity.

SURGICAL CARE IMPROVEMENT PROJECT AND SURGICAL SITE INFECTION

Surgical procedures possess inherent risk. The dangers of surgery, some of which are readily apparent, are demonstrated in full by a brief review of the arena in which many surgical advances developed: war theaters through the centuries. Until World War II, disease and nonbattle injuries caused an inordinate amount of morbidity and mortality, and much of what was labeled "war pestilence" was infectious in nature. In the Civil War in the United States (U.S.) and World War I, for example, for every soldier who died in combat, 7 soldiers died of disease or postsurgical complications such as surgical site infections (SSIs). After sulfanilamide and penicillin were discovered, surgeons began to hope that infection-free surgery might be possible.¹

During the 1950s and 1960s, researchers studied perioperative antibiotics arduously. They produced high-quality laboratory and clinical evidence that supported the idea that appropriate antibiotic administration decreased SSI rates.¹ The Centers for Disease Control and Prevention (CDC) has been monitoring nosocomial infections via the National Nosocomial Infections Surveillance system (NNIS, now called the National Health Care Safety Network) since 1970. The CDC has found little uniformity in how hospitals addressed SSI. Prevention has not been not a priority; most patients have received organism-appropriate antibiotics, but the timing of doses has been erratic. In one study, only 56% of surgical candidates received antibiotics at the most ideal time—within 1 hour of incision.²

Despite medical and surgical advances, the threat posed by SSIs persists. Data collected as recently as 2011 indicate that approximately 750,000 SSIs occur annually at a cost of more than $2 billion to the U.S. health care system.³ An SSI that extends a hospital stay by a week or more can triple the cost of care.⁴ Numerous other adverse outcomes are possible after surgery including failure to resume crucial preoperative medications, thromboembolism, or prolonged and unnecessary catheterization. This section focuses on SSI, a continuing serious concern that is influenced by a constellation of factors as shown in Table 1.

Table 1. Risk Factors for Surgical Site Infection

Source: Reference 2

THE SURGICAL CARE IMPROVEMENT PROJECT

In 2002, the Centers for Medicare & Medicaid Services (CMS) partnered with more than 30 national organizations—including the American Hospital Association, CDC, Institute for Health Care Improvement, and The Joint Commission—to standardize surgical quality improvement. In the National Surgical Infection Prevention Project (SIP), hospitals began collecting data in July 2004. The project was later renamed The Surgical Care Improvement Project (SCIP) and broadened to include performance measures that would reduce postoperative surgical complications. The program's goal was to reduce surgical complications by 25% by 2010.^2,3

A technical expert panel developed a mechanism through which hospitals could address publicly reported individual SCIP core measures.⁵ Core (meaning central or most important) measures are evidence-based criteria for specific conditions that gauge timeliness and effectiveness of care. These describe specific actions that, when consistently applied, contribute to successful outcomes. Publicly reported quality measures have the potential to not only improve patients' outcomes, but also affect health care providers' business models. Core measures are costly to collect and report; if a hospital's performance falls short, corrective actions are equally time-consuming and costly to implement. To a certain extent, cost exerts pressure on hospitals to perform better, but the public nature of these measures is a larger driver. Poor scores may convince patients to seek health care services elsewhere.³

SCIP now consists of nine measures, all of which address factors that can compromise outcomes, shown in Table 2. Three core measures pertain to preventing health care-associated infections (HAIs) and are of specific interest to health-system pharmacists:

• Use of prophylactic antibiotics appropriate for the patient's specific procedure.

• Initiation of prophylactic antibiotics no less than 1 hour before surgical incision (or within 2 hours in patients receiving vancomycin or fluoroquinolones).

• Discontinuation of prophylactic antibiotics within 24 hours after surgery completion
(within 48 hours for cardiothoracic surgery).^6-9

These core measures are quite specific and the entire health care teams needs to be aware of them. In terms of surgery-related HAIs, pharmacists must appreciate four specific components: antibiotic selection, timing of initial dose, intraoperative re-dosing recommendations, and antibiotic discontinuation.

Table 2. 2015 SCIP Measures

Source: Adapted from references 3 through 6

Abbreviation used: VTE - venous thromboembolic

Antibiotic Selection

Antibiotics, when used properly, augment proper aseptic technique, and are an additional protection against infection. However, prophylactic antibiotics create some risks including adverse reactions and development of antibiotic-associated diarrhea. Antibiotic overuse can increase bacterial resistance.⁸

An appropriate prophylactic antibiotic has five properties⁹:

1. It is effective against microorganisms anticipated to cause postoperative infection in the specific wound type and the hospital's geographic location.

2. It will achieve adequate local tissue levels that exceed the minimum inhibitory concentration needed for the most likely infecting organism, and maintain those levels from incision through wound closure.

3. It will cause minimal adverse effects.

4. The cost will be reasonable.

5. It will be unlikely to cause or contribute to increasing organism virulence.

Staphylococcus species cause infection in the majority of procedures that do not violate mucosa or hollow viscera (the small and large intestines, stomach, esophagus, bladder, and uterus). . Often, a cephalosporin fulfills these criteria and is a preferred agent. The SCIP recommendations include an extensive, detailed chart that describes preferred antibiotics by surgical site. Adequate doses are those calculated with consideration of patient weight or body mass index.^8,9

Timing of Initial Dose

SCIP specifies timing of antibiotic administration because presence of the drug at the surgical site before the surgeon makes the first incision reduces the likelihood of SSI. Studies have confirmed that when antibiotics are administered between 30 minutes and 2 hours before incision, infection rates are very low. National guidelines recommend beginning antibiotic infusion within 60 minutes of incision (or within 2 hours in patients receiving vancomycin or fluoroquinolones).⁹

Intraoperative Redosing

Some surgical procedures can be lengthy. When the operative period is longer than the half-life of the prophylactic antibiotic or there is excessive blood loss (i.e., more than 1,500 mL), re-administration of the antibiotic may be needed to ensure adequate coverage throughout the procedure. Currently, 2013 clinical practice guidelines suggest administering a second dose of the same antibiotic at intervals of 2 times the drug's half-life. Pharmacists who work in the surgical arena should have copies of the guidelines available for ready reference at all times. Clinicians need to refer to the document's redosing recommendation for the patient's specific procedure and the antibiotic being used.⁹

Antibiotic Discontinuation

Studies have also demonstrated that administering antibiotics after the surgeon closes the incision is unnecessary, so SCIP recommends discontinuing antibiotics within 24 hours. If adequate tissue levels are achieved during the procedure, the antibiotic should not be needed after the procedure is complete.⁹ However, certain surgeries, such as those for perforated appendix, may require active treatment with antibiotic continuation needed after surgery.⁹

Additional Notes

Antibiotic prophylaxis is used in all surgical incisions, but patients who have wounds classified as contaminated (open wounds after injury, viscus spillage, subject to break in sterile technique, or incision through inflamed tissue) or dirty (traumatic in nature, necrotic or clearly infected) will need to receive continuing therapeutic antibiotic treatment.^4,10,11 More serious wounds are associated with infection rates of up to 10%.¹¹

Other nonantimicrobial interventions can reduce SSIs and may require the pharmacy team to mobilize. Controlling the patient's intraoperative temperature, administering supplemental oxygen, and aggressively hydration have been shown to decrease infection rates, although more research is needed.^12-15 Aggressive perioperative blood glucose control with intravenous insulin in patients undergoing cardiac operations decreases SSI rates, and avoiding intraoperative hyperglycemia is critical.^11,16

Have these reporting measures actually decreased infection rates? Stulberg et al. found that none of the individual SCIP measures was significantly associated with a lower probability of infection. Composite analysis looking at all measures collectively found lower infection rates.⁶ Another study found that SSI risk varied by patient, procedure, and antibiotic properties but was not significantly associated with prophylactic antibiotic timing.¹⁷

Surgical suite staff cannot pick and choose among these measures. They need to implement all of them. Attention to the full set of metrics collectively appears to improve care and outcomes.

MALIGNANT HYPERTHERMIA

Rare and life-threatening, MH is associated with an autosomal-dominant calcium channel mutation. Ordinarily, most MH-susceptible (MHS) individuals are unaware of their condition. However, exposure to volatile anesthetics or depolarizing muscle relaxants such as succinylcholine (other drugs have also been implicated as seen in Table 3) disrupts intracellular calcium homeostasis, allowing uncontrolled calcium release from the sarcoplasmic reticulum. A skeletal muscle metabolic crisis rapidly develops as calcium builds in this tissue and may progress to a fatal hypermetabolic state called MH crisis.^18,19 Until the 1970s, MH was associated with a mortality rate of 70% to 80%.^20,21

Table 3. Potential Triggers of Malignant Hyperthermia

Source: Reference 2

Abbreviations used: MH – malignant hyperthermia; SSRIs – selective serotonin reuptake inhibitors; SNRIs – serotonin–norepinephrine reuptake inhibitors; MAOIs – monoamine oxidase inhibitors

The caffeine-halothane contracture test (CHCT) remains the gold standard for diagnosing MHS) individuals and requires a muscle biopsy. It is based on the observation that MH muscle samples were more sensitive to the contracture-inducing properties of caffeine, caffeine with halothane, or halothane alone, than normal muscle.¹⁹ Very few centers are capable of performing the test (only four in the U.S. and 30 in the entire world). Since 2001, building on research that identified MH-associated mutations in the ryanodine receptor gene, the European Malignant Hyperthermia Group (EMHG) has maintained a guideline for genetic testing to identify patients with MH susceptibility. In July 2015, EMHG updated the guideline for the diagnostic pathway for patients with potential increased risk for developing malignant hyperthermia.¹⁹

For obvious reasons, most MH occurs in the surgical suite when patients are challenged with anesthesia and muscle relaxants. Due to its tendency to progress rapidly, MH is considered an emergency requiring immediate treatment.¹⁹

Epidemiology and Presentation

MH affects children and young adults of all races, but males are affected 2.5 to 4.5 times more often than females.²⁰ The true genetic prevalence of MH is probably higher than the estimated incidence of 1 case for every 2,000 individuals for several reasons:

• Many susceptible people never receive an MH- triggering drug and never develop MH.
• Some susceptible people are exposed to MH-triggering agents but experience only mild reactions that resolve quickly and spontaneously; their healthcare providers either do not see the symptoms or interpret them as something else.
• MH follows an autosomal-dominant inheritance pattern in humans, so its prevalence is increasing.²²

MH's symptoms range from abortive courses (episodes that start insidiously, but for some reason have lighter symptoms or end quickly) to fulminant MH crises.²²

In the surgical suite, signs of impending MH begin with excessive carbon dioxide (CO₂) production. End tidal CO₂ concentrations increases or hyperventilation develops while the patient is breathing spontaneously. Between 50% and 80% of patients develop tachycardia, supraventricular or ventricular arrhythmia, and isolated masseter (jaw) spasm if succinylcholine has been used or generalized muscular rigidity with other agents.²² Additional signs include profuse sweating and mottled (spotted or blotchy) skin.

As the crisis progresses, patients develop hallmark cyanosis due to oxygen consumption that is 3-fold greater than normal. Although the condition is called hyperthermia, temperature spikes to 38.8°C (102^oF) or more often occur relatively late or are prevented altogether if the anesthesiologist recognizes the problem and starts treatment quickly. Untreated, MH progresses to rhabdomyolysis and its cascade of hyperkalemia, elevated creatine phosphokinase, and myoglobinemia. Acute renal failure becomes a strong possibility as the kidneys strain to eliminate myoglobin, and at end stage, multiorgan failure and circulatory collapse occurs.^20,22

MH is managed as an emergency, and requires specific monitoring and treatment in the postacute phase.

Medical Emergency

MH treatment follows the same protocol employed for any drug reaction, with the situation being complicated if the patient is presently undergoing surgery and is unconscious. Surgical suite staff need to be prepared to act quickly, modifying their approach based on the patient's clinical presentation and unique needs. Staff should take the following actions²²:

• Withdraw the offending agent as quickly as possible.
• Call for help if necessary, often making the call to the pharmacy response team.
• Give dantrolene 2.5 mg/kg (1 mg/lb) and repeat every 5 minutes until the patient's respiratory symptoms are stable. Large doses (more than the recommended 10 mg/kg) may be required for patients with persistent contractures or rigidity. Note that 10 mg/kg is not a ceiling dose; however, do not exceed 30 mg/kg.

• Assess the need for continuing anesthesia, and if surgery must continue, start intravenous opioids, sedatives, and if necessary, nondepolarizing muscle relaxants. End the surgery as quickly as possible.

 

• Concurrently, the anesthesiologist should remove the vaporizer used to administer the volatile anesthetic, replacing it with 100% oxygen at maximum fresh gas flow to restore end tidal pCO₂ to within normal limits.

The hydantoin derivative dantrolene, a specific ryanodine receptor antagonist, decreases calcium loss from skeletal muscle's sarcoplasmic reticulum and restores normal metabolism.

Injectable dantrolene is available in 3 forms. Dantrium 20 mg vials that must be diluted in 60 mL of sterile water before administration (do not use diluents that contain bacteriostatic agents). Revonto 20 mg and Ryanodex 250 mg are packaged with their own solutions for reconstitution. The difference between the products is significant. Ryanodex reconstitution yields a more concentrated solution with 250 mg dantrolene suspended in 5 mL of sterile water for injection in less than 30 seconds; it can be administered in less than 1 minute. An initial treatment dose of dantrolene of 2.5 mg/kg for an 80 kg patient requires only 4 mL (200 mg). For Dantrium and Revonto, reconstitution produces 60 mL, a considerably larger volume that cannot be administered as quickly.^23-26

Pharmacists need to remember that calcium channel blockers, when given with dantrolene, may precipitate severe hyperkalemia and should be avoided. Although dantrolene has few, rare adverse effects, pharmacists should be aware of them. They include prolonged breathing problems, tissue necrosis after extravasation, nausea, vomiting, headache, and dizziness.²⁴

If the patient continues to display symptoms following the cumulative administration of 10 doses of dantrolene, MH is an unlikely diagnosis.^25,26 Table 4 describes additional supportive care.

Table 4. Additional Interventions for Acute MH

Source: References 22, 24-26

Abbreviations used: MH – malignant hyperthermia.

Postacute MH

Patients who experience an episode of MH should be relocated to the intensive care unit for at least 24 hours. During that time, dantrolene 1 mg/kg every 4 to 6 hours or 0.25 mg/kg/h should be administered continuously for at least 24 hours and longer if they remain symptomatic. Clinicians must monitor for damage to the kidney. Table 4 describes standard interventions during this time.^22-26

Patients should be referred for counseling and assessment to ensure they do not experience MH again.

Treating an MH reaction early usually results in complete recovery, but a small number of patients with MH die from organ failure annually. Every surgical suite should have a poster posted in a prominent location to guide staff through the appropriate treatment steps should a patient develop MH.

Additional Notes

The Malignant Hyperthermia Association of the United States (MHAUS, www.mhaus.org) educates the public and health care workers about MH and supports relevant research and education. The organization also provides a 24-hour hotline [(800) MH-HYPER or (800) 644-9737] to answer questions about MH and assist treating clinicians with acute cases. The group also encourages reports to the North American registry of acute MH cases, a database that researchers can use to further advance understanding of the condition.²⁷

MH management has improved, as reflected by mortality declining from 80% to less than 5%. Improved treatment and better resources have made the difference.²⁸

USING ALVIMOPAN SAFELY

Alvimopan (Entereg) is a peripherally acting μ-opioid receptor antagonist indicated to accelerate the time to upper and lower gastrointestinal (GI) recovery following surgeries that include partial bowel resection with primary anastomosis (connection of the healthy sections of the colon or rectum after a cancerous or otherwise diseased portion has been surgically removed). Clinical trials of alvimopan identified a potential for patients to develop myocardial infarction with long-term use, a potential problem that the U.S. Food and Drug Administration (FDA) addressed by requiring a risk evaluation and mitigation strategy (REMS) program.^29,30 As a result, alvimopan is available only to hospitals that perform surgeries that include a bowel resection and dispensed by pharmacies that are enrolled in the E.A.S.E. ENTEREG® REMS Program.

Hospital pharmacies may receive requests to use alvimopam for off-label uses. These are usually based on small studies using alvimopan in cystectomy.^31-34 Pharmacists should follow their hospitals’ procedures for approval of off-label drug requests, but cannot exceed the dosing parameters for alvimopan approved by the FDA.

REMS Programs

The concept of risk evaluation and mitigation is rooted in the Food and Drug Administration Amendments Act of 2007, which expanded the FDA’s authorities and responsibilities. The authority to require a REMS was designed to improve drug safety. The FDA can direct manufacturers to design and implement a REMS to ensure that a drug or biological product’s benefits outweigh its risks. The FDA can require a REMS as a condition for approval of a new product or for an approved product if new safety concerns are identified. REMS are designed to manage a known or potential serious risk associated with drugs or biologics.³⁵

Every REMS is tailored to the drug or biologic it addresses. Depending on the agent and its adverse event profile and monitoring requirements, the FDA may require any or all of the items listed in Table 5.³⁵

Table 5. Possible Components of FDA-Mandated REMS Plans

Source: References 35

Abbreviations used:ETASU –elements to assure safe use; FDA – U.S. Food and Drug Administration; PPI – patient package insert; REMS, Risk Evaluation and Mitigation Strategy

The Entereg EASE Program

The Entereg Access Support & Education (EASE) program (http://www.enteregrems.com/) is a product-specific REMS designed to ensure that prescribers and patients use alvimopan in accordance with the FDA-approved label.^29,30 This program is intended to reduce the potential risk for myocardial infarction (MI) with long-term use of this drug. Its 3 main components include the following:

• The manufacturer must ensure the hospital receives the EASE REMS program kit and all health care practitioners responsible for ordering, dispensing, or administering alvimopan have been educated on alvimopan's benefits and risks.

• The certified hospital pharmacy has pharmacy systems, order sets, protocols, and/or other measures in place to limit the use of alvimopan to inpatient settings and a maximum of 15 doses.

• The certified hospital pharmacy will not dispense alvimopan to outpatients and will not transfer alvimopan to any hospital pharmacy not enrolled with the EASE REMS Program.

Dear Health Care Provider Letter

The key point in alvimopan's Dear Health Care Provider Letter is that this drug is indicated for short-term use only. The letter describes a 12-month study (the length of study that the FDA considers the basis of long-term evaluation) in which 805 patients treated with opioids for chronic pain received either 0.5 mg alvimopan (n = 538) or placebo (n = 267) twice daily. Alvimopan-treated patients were more likely to experience myocardial infarction than placebo-treated patients, with most events occurring between 1 and 4 months after treatment initiation. The manufacturer indicates that this imbalance has not been observed in other alvimopan studies and no causal relationship has been established definitively.^29,36

In keeping with current FDA requirements, the Dear Health Care Provider Letter also provides information to remind health professionals to report adverse events. To report suspected adverse reactions contact Cubist Pharmaceuticals at 1-877-CUBIST-6 (1-877-282-4786) or contact the FDA at 1-800-FDA-1088 (1-800-332-1088) or at www.fda.gov/medwatch/default.htm .

Prescriber and Pharmacist Brochure

Cubist Pharmaceuticals also provides a 3-page Prescriber and Pharmacist Information Brochure (located here). Table 6 describes the brochure's main messages.³⁰

Table 6. Prescriber and Pharmacist Brochure Summary

Source: References 30

Abbreviations used:EASE – Entereg Access Support & Education Program; REMS – Risk Evaluation and Mitigation Strategy.

The brochure highlights several important sections of the complete prescribing information. First, it reminds health care providers that patients who receive more than 3 doses of an opioid within the week before surgery may be more sensitive to alvimopan. They may experience unwanted abdominal pain, nausea and vomiting, and diarrhea.

Next, the brochure addresses organ impairment and serious contraindications. Alvimopan is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, complete gastrointestinal obstruction, pancreatic or gastric anastomosis, or in patients who have had surgery for correction of complete bowel obstruction.

The brochure reports that alvimopan's most common adverse reaction—dyspepsia—occurs at an incidence of 1.5% or more.

Additional Notes

Pharmaceutical manufacturers evaluate their products' safety throughout their lifecycles. During clinical trials and product development, manufacturers often anticipate safety concerns and the possibility that the FDA will require a REMS. When serious potential risks are identified, manufacturers develop effective risk management strategies that are as flexible as possible.³⁵

In the surgical space, pharmacists need to be aware of the EASE program. Its efforts are directed at health professionals to ensure that appropriate patients receive the medication in the hospital, 15 doses or fewer are administered, and that MI risk is minimized.

LOCAL ANESTHETIC TOXICITY

Unlike general anesthetics that act systemically, local anesthetics (LAs) block sensations (especially pain) only in the affected area. Anesthesiologists and physicians often target specific nerve pathways or induce paralysis when they perform specific procedures. They may employ LAs for topical or surface anesthesia, infiltration, plexus block, epidural block, or subarachnoid block.^37-39

Structurally related to cocaine, synthetic LAs are rarely abused and produce no hypertension and very little vasoconstriction. Often, LAs are administered with another drug to decrease bleeding (e.g., lidocaine) or to decrease the anesthetic's acidity and quicken its onset of action (e.g., sodium bicarbonate). Use of LAs has increased in the last decade as minimally invasive and ultrasound-guided techniques have grown in popularity. These techniques improve postoperative analgesia and lead to better perioperative outcomes.^37-39

A large number of LAs are now available and are classified by chemical structure either as amides or esters.^37-39 Table 7 lists some of the currently used LAs in these two categories. Many health professionals remember an agent's classification in this way: amides generally have 2 i's and esters have 1. Procainamide—an ester with 2 i's—is the sole exception. Usually, patients who have an allergy or hypersensitivity to an amide LA do not cross-react to ester LAs.⁴⁰

Table 7. Local Anesthetics

Local anesthetic systemic toxicity (LAST) usually results from elevated LA plasma concentrations.^37-39 In fewer than 1% of patients who receive LA, systemic toxicity can be life-threatening.³⁹

Most experts agree that LAs have the greatest potential to cause adverse reactions when prescribers use inappropriate doses or routes or use a faulty injection technique. However, unintended reactions to local anesthetics are possible even when dose and route are appropriate. Patients with renal or hepatic impairment, respiratory acidosis, preexisting cardiac block, hypoxia, or ischemic heart disease are at elevated risk for reaction. Patients who are pregnant, very young, or very old also are more likely to have adverse reactions to LA.^37-39

The most common cause of LAST is inadvertent intravascular injection, which can occur even if the anesthetic was administered within the recommended dose range.^37-39

Clinical Presentation of LAST

LAST's signs, symptoms, and timing are capricious, and a high level of vigilance is crucial since early detection is associated with successful outcomes. One can think of LAST as a progressive biphasic reaction that starts in the central nervous system (CNS) and progresses to the cardiovascular system, although presentations vary. Both systems are very sensitive to changes in tissue electrophysiology. Symptoms most often occur within 50 seconds of LA injection but can be delayed for an hour or more after injection. Red flags in any patient who has received an LA include altered mental status and cardiovascular instability.³⁸

CNS symptoms are usually the first to develop. They may be subtle, or even absent altogether. CNS excitation causes agitation, confusion, twitching, and seizures. CNS depression may also occur and can cause drowsiness, obtundation, coma, or apnea. In addition, patients may develop nonspecific neurologic symptoms including metallic taste, circumoral paresthesias (burning, prickling, or formication around the mouth), diplopia, tinnitus, and dizziness.⁴¹

In the heart, LAST is manifested through conduction and contractility abnormalities. Both tachyarrhythmia and bradycardia are possible. Hypotension or bradycardia may be a symptom of severe local anesthetic toxicity. In severe cases, progressive hypotension and bradycardia can cause asystole. Ventricular ectopy, multiform ventricular tachycardia, and ventricular fibrillation are common problems.

One critical point to remember is that LAST, especially when caused by potent and long-acting LAs, is mechanistically different from cardiac arrest due to ischemia or a re-entrant arrhythmia. This makes LAST somewhat resistant to traditional resuscitation methods.^38,39

Mechanisms of Toxicity

The actual cause of LAST is not fully understood at this time, though it may be related to the specific LA's mechanism of action: A flux of sodium ions across plasma membranes initiates and propagates axonal action potentials. LAs bind to any of nine specific voltage-gated sodium (NaV) channels and reduce sodium ion flux during depolarization in cardiac, nerve, and skeletal muscle tissues. LAs appear to cause toxicity mainly when they block cardiac sodium channels. Other proposed mechanisms include interference with ionotropic and metabotropic signaling systems, and effects on mitochondrial metabolism and oxidative phosphorylation that prevent electron transport and the ability to use fatty acids as fuel in cardiac myocytes.³⁹

In the CNS, LAs block inhibitory pathways in the cerebral cortex, causing excitation. Now unfettered, facilitatory neurons begin to work or function unopposed, increasing excitatory activity further and leading to convulsions. As the LA dose increases, both inhibitory and facilitatory circuits are inhibited, resulting in generalized CNS depression.³⁹

As LA toxicity develops, hypercarbia and/or acidosis also decrease LA plasma protein binding. Elevated carbon dioxide levels and falling pH also increase the available free drug to diffuse into the brain. Conversely, acidosis increases the cationic form of the LA, which decreases its diffusion rate through lipophilic cell membranes, a situation called ion trapping. The anesthetic gets trapped in the intracellular space, and cannot be eliminated. Clinically, comorbid hypercapnia and acidosis create a precarious situation. Seizures and CNS depression can lead to hypoventilation and respiratory acidosis; decreased cardiac output leads to metabolic acidosis, which further exacerbates the CNS and cardiac toxicity.^37-39

Anesthetics have different affinities for NaV channel isoforms, and various cardiac and nerve isoforms probably contribute to differences among LAST syndromes. LAs with short clinical durations of action and lower potencies (e.g., lidocaine and mepivacaine) tend to depress cardiac contractility without producing cardiac arrhythmias. Those with longer durations of action and greater potencies (e.g., bupivacaine, levobupivacaine, and ropivacaine) seem more likely to produce conduction defects with cardiac arrhythmias, with or without evidence of reduced contractile function.³⁹

Prevention of LAST

Since LAs have the greatest potential to cause LAST if inappropriate doses or routes are used or the health professional's injection technique is faulty, prevention of most (but not all) reactions is possible. Table 8 describes reasonable interventions that may reduce the likelihood of LAST occurring.

Table 8. Steps for Preventing LAST

Source: References 38, 42, 43

Abbreviations used:BPM, beats per minute; LA, local anesthetic

Prompt Treatment: Assisted Ventilation and Circulatory Support

At the first sign of LAST, the surgical team should not inject any more LA, secure the patient’s airway, ventilate with 100% oxygen, and call for help. If the patient does not have intravenous (IV) access established, a team member should insert an IV line. Team members should have a defibrillator ready and retrieve the crash cart or emergency box. Next, someone should secure an LA toxicity kit (20% fat emulsion, off-label use). This is often a role for the pharmacy response team.^41,42,44

The LA toxicity kit consists of four 250-mL bags of 20% fat emulsion. The kit was designed with consideration of the potential for recurrence of cardiovascular instability after initial successful reversal of MH. Clinicians may need access to a total dose of 1000 mL. The kit also includes a 3-way lock, two 50-mL Luer-lock syringes, intravenous access and venoclysis equipment, and the protocol sheet.⁴⁵ Table 9 describes various interventions and their purposes.

Table 9. Management of LAST

Source: References 38, 41, 42, 44, 46, 47 and 48

Abbreviations used:CNS – central nervous system; LA – local anesthetic; LAST – local anesthetic system toxicity

In treatment-resistant cases of LAST in which there is inadequate response to epinephrine and other standard therapies, cardiopulmonary bypass should be considered as a bridging therapy until tissue levels of LAs have cleared.^37-39

Additional Notes

LAST is a growing concern. Anesthesiologists are trained to watch carefully for LAST. Other health professionals—those who work in offices, outpatient facilities, and small surgical centers—need education so that misdiagnosis and underreporting can be reduced. Knowledge about LAs and management of complications is important. Prevention strategies can reduce the rate of LAST, but will not eliminate it. Pharmacists can provide comprehensive education and ensure that the crash cart is augmented with a LAST rescue kit.

SUMMARY

Pharmacists' can expand their roles in the perioperative setting by having an antibiotic surveillance program that addresses SCIP measures. All pharmacists who work with the surgical suite should be prepared to treat malignant hyperthermia and have dantrolene available. Alvimopan should be available preoperatively, and pharmacists need to be familiar with the FDA's approved REMS, limiting dosing to 15 postoperative doses during hospitalization. In the event that a patient develops LAST, rapid response with all the necessary components is critical.

References

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3. Cataife G, Weinberg DA, Wong HH, Kahn KL. The effect of Surgical Care Improvement Project (SCIP) compliance on surgical site infections (SSI). Med Care. 2014;52(2)(suppl 1):S66-S73.

4. Tillman M, Wehbe-Janek H, Hodges B, Smythe WR, Papaconstantinou HT. Surgical care improvement project and surgical site infections: can integration in the surgical safety checklist improve quality performance and clinical outcomes? J Surg Res. 2013;184(1):150-156.

5. The Joint Commission. Surgical Care Improvement Project Available at: http://www.jointcommission.org/surgical_care_improvement_project/. Accessed March 8, 2016.

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9. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health-Syst Pharm. 2013;70:195-283.

10. Classification of surgical wounds. Master of Medicine.com http://masterofmedicine.com/classification-of-surgical-wounds/. Accessed July 22, 2015.

11. Furnary AP, Kerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67(2):352-360.

12. Kurz A, Sessler DI, Lenhardt RA. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med. 1996;334(19):1209-1215.

13. Grief R, Akca O, Horn E-P, et al. Supplemental perioperative oxygen to reduce the incidence of surgical wound infection. N Engl J Med. 2000;342(3):161-167.

14. Melling AC, Ali B, Scott EM, et al. Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomized controlled trial. Lancet. 2001;358:876-880.

15. Sessler DI, Akca O. Nonpharmacologic prevention of surgical wound infections. Clin Infect Dis. 2002;35(11):1397-1404.

16. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg. 1997;63(2):356-361.

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