Multimodal Pain Management

Multimodal Pain Management

35. W.W., a 36-year-old male, arrives at the ambulatory surgery center for an inguinal hernia repair. This procedure will be performed under local anesthesia, with sedation as needed, and is expected to be completed within 30 minutes. His medical and surgical histories are unremarkable. He is not currently taking any medication and reports no drug allergies. Following discharge from the ambulatory surgery center, how should W.W.'s postoperative pain be managed?

In general, one would expect that the greater the magnitude of the surgical trauma, the greater the patient's postoperative pain.¹⁴⁵ For minor surgical procedures (e.g., inguinal hernia repair, breast biopsy), there is minimal surgical trauma, and the patient goes home shortly after surgery. For intermediate surgical procedures (e.g., total abdominal hysterectomy, laparoscopic cholecystectomy), short-term hospitalization is often necessary to observe the patient's recovery and manage his or her pain. Patients undergoing major surgery (e.g., bowel resection, thoracotomy) experience a significant surgical stress response that can significantly increase postoperative morbidity. Effective pain management is essential.

 

If pain is mild in intensity, a nonopioid analgesic such as acetaminophen or an NSAID is appropriate. If pain is moderate in intensity or not controlled with acetaminophen or an NSAID, a low-potency opioid combination (e.g., acetaminophen with hydrocodone or codeine) is used. When pain is moderate to severe in intensity, a more potent opioid (e.g., morphine, oxycodone) is necessary. If a fixed combination of opioid and nonopioid is used, the total daily dose administered to the patient is limited by the maximum allowable daily dose of the nonopioid (e.g., acetaminophen, ibuprofen).

 

Multimodal or “balanced” analgesia is often used to provide postoperative analgesia. It is difficult to optimize postoperative pain relief, to the point of achieving normal function, by using one drug or route of administration. By using two or more drugs that work at different points in the pain pathway, additive or synergistic analgesia can be achieved and adverse effects reduced because doses are lower and side effect profiles are different. Opioids are a mainstay of analgesic therapy for moderate-to-severe pain. However, opioids are often associated with intolerable adverse effects (e.g., nausea, vomiting, constipation, itching, sedation). Maximizing the use of nonopioid analgesics generally results in less need for opioids and improved analgesia (Table 9-20).^{145,146,169-172} When compared to morphine alone, the addition of an NSAID following major surgery reduces pain intensity and 24-hour morphine consumption. As a result, the incidence of morphine-related adverse effects of nausea, vomiting, and sedation is also reduced. Although the risk of surgical bleeding from nonselective NSAIDs is low, the risk can be increased in certain settings (e.g., after tonsillectomy).¹⁶⁹

 

Table 9-20 Commonly Used Analgesic Drugs and Nonpharmacologic Techniques for Postoperative Pain Management

Type of Agent Examples Potential Adverse Effects Local anesthetics Peripheral nerve block, tissue infiltration, wound instillation Tingling, numbness, residual motor weakness, hypotension, CNS and cardiac effects from systemic absorption NSAIDs Ketorolac (IV, IM, oral), ibuprofen (oral), naproxen (oral), celecoxib (oral) GI upset, edema, hypertension, dizziness, drowsiness, GI bleeding, operative site bleeding (not celecoxib) Other nonopioids Acetaminophen (oral, rectal) GI upset, hepatotoxicity Nonpharmacologic Transcutaneous electrical nerve stimulation, acupuncture Skin irritation, discomfort   Ice or cold therapy Excessive vasoconstriction, skin irritation   Distraction, music, deep breathing for relaxation   Less potent opioids Hydrocodone + acetaminophen, codeine or oxycodone + acetaminophen Nausea, vomiting, constipation, rash, sedation, mental confusion, hallucinations, respiratory depression More potent opioids Morphine (IV, epidural), hydromorphone (IV, epidural), fentanyl (IV, epidural), oxycodone (oral) Nausea, vomiting, pruritus, constipation, rash, sedation, mental confusion, hallucinations, respiratory depression CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs; IV, intravenous; IM, intramuscular; GI, gastrointestinal. Adapted from references 145, 146, and 169, 170, 171, 172.

 

For W.W., the anticipated surgical trauma is minor, and he will recover at home. The surgeon will inject a long-acting local anesthetic (e.g., bupivacaine) into the tissues surrounding the surgical field. This will provide intraoperative anesthesia at the surgical site and postoperative analgesia until the effects of bupivacaine wear off. Then, W.W. will likely require a less potent opioid (e.g., hydrocodone, codeine) combined with acetaminophen for pain control. If his pain is not controlled or his pain is mild in intensity, W.W. may take an NSAID (e.g., ibuprofen 200 or 400 mg Q 4–6 hr PRN or naproxen 220 mg Q 12 hr PRN).

 

 

Economic Issues

It is still common to find several anesthesia-related medications (e.g., sevoflurane, rocuronium) on an institution's top 25 expenditure list. Because of this, these medications are often targeted for cost-containment activities (e.g., appropriate flow rate for sevoflurane, use of vecuronium in place of rocuronium when appropriate).^173-177 Although many anesthetic agents do not appear to be excessively expensive when looking at individual patient use, large dollar savings can be realized because of the thousands of patients that are anesthetized per year in a hospital.

 

Value-Based Anesthesia Care

When trying to reduce costs in the perioperative setting, one should not focus solely on using the least expensive technology, piece of equipment, or drug. This strategy can lead to unacceptable patient outcomes and higher total costs. The importance of looking at the “big picture” has been recognized by the anesthesiology profession since the early 1990s when they put forth the concept of value-based anesthesia care, which seeks the best patient outcomes at the most reasonable costs. The advantages and disadvantages of the technique or drug are balanced against all costs associated with the surgical experience.¹⁷⁸

Total Costs of Surgical Stay

In one study, anesthesia costs, including medication use, accounted for 6% of the total costs for inpatient surgery, with approximately 50% being variable. Hence, modifying medication selection can impact, at most, 3% of the total costs associated with surgery. However, OR costs, including the costs of the PACU, accounted for 37% of the total costs of surgery, with approximately 44% being variable. Therefore, modifying practices that influence these costs can impact total cost by up to 16%.¹⁷⁹ In another study, labor costs were estimated to be two orders of magnitude greater than anesthesia maintenance costs for a 60-minute outpatient procedure; therefore, a major component of cost-containment efforts should be directed at the reduction of labor costs by streamlining OR time and shortening PACU discharge time.¹⁸⁰ Methods to reduce a patient's PACU stay may allow personnel reductions and/or reassignment of staff during slow periods. These studies highlight the opportunity for cost reduction in the perioperative setting by focusing on nonmedication costs and support the concept of fast-track anesthesia.

 

Fast-Track Anesthesia

Throughput is a major issue in most hospitals today. The perioperative setting is often targeted as needing improvement. Fast-track anesthesia, if successfully implemented, can help with throughput issues. The goal of fast tracking is to accelerate the movement of the patient through the perioperative experience (OR, PACU, and/or ICU). It has been promoted to improve patient satisfaction, to improve OR and PACU efficiency, and to lower the costs of the surgical experience. Several developments have facilitated the fast-track process and include the wide-scale use of less invasive surgical procedures (e.g., laparoscopy), the incorporation of new monitoring techniques to allow better titration of anesthesia (e.g., “consciousness” monitors),¹⁸¹ and the use of short-acting, fast-emergence anesthetic agents to reduce wake-up times and drug hangovers. Although medication costs may be higher with fast-track anesthesia, fast tracking can improve clinical and financial outcomes in both inpatient and outpatient settings. Fast tracking cardiac surgery patients has resulted in quicker extubation, reduced length of stay, reduced ICU readmission rate, and a 25% cost reduction.^182,183 Furthermore, fast-track cardiac surgery patients have a decreased health care resource usage for at least 1 year following discharge.¹⁸⁴ In a landmark outpatient study, fast tracking was implemented in five surgical centers and resulted in annual net savings from $50,000 to $160,000, with no significant differences in patient outcomes.^185,186 In this study, outpatients meeting a well-defined set of criteria were allowed to skip phase I recovery and proceed directly to phase II from the OR. Phase I recovery can be considered an ICU-type environment. Patients are taken here from the OR to recover hemodynamically and fully regain consciousness; this requires intensive nursing care (usually one nurse to two patients). Once patients are awake, hemodynamically stable, and able to sit upright, they are moved to phase II recovery to finish the recovery process. In this setting, the nurse-patient ratio is 1:3, or greater if nurse assistants are employed. The low-solubility, volatile inhalation agents (desflurane, sevoflurane) are ideally suited for fast tracking in the outpatient setting.^181,187

 

Thus, the goal for the cost-effective use of medications in the perioperative setting is a net reduction in the cost of surgical procedures (either the result of a lower overall medication cost or process modifications such as fast tracking) by taking advantage of the medications' properties and keeping in mind that patients' outcomes should not be negatively impacted and, ideally, should be improved.

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Epidural Analgesia

Epidural Analgesia

29. T.M., a 69-year-old man, enters the surgical ICU after surgery for colorectal cancer (lower anterior resection, urethral stents, ileorectal pull-through). His pain is managed through a lumbar epidural catheter. What are the benefits and risks of epidural analgesia, and why was this approach to postoperative analgesia chosen for T.M.?

Advantages and Disadvantages

Epidural analgesia can offer superior pain relief over traditional parenteral (IM and IV PCA) analgesia.¹⁵⁸ Continuous epidural infusions offer an advantage over intermittent epidural injections because peak and trough concentrations of drugs are avoided. Epidural catheter placement is an invasive procedure that can result in unintentional dural puncture, causing postdural puncture headache, insertion site inflammation or infection, and, rarely, catheter migration during therapy and epidural hematoma.¹⁵⁵

 

Patient Selection

Epidural analgesia should be chosen based on the need for good postoperative pain relief and reduced perioperative physiological responses. Postoperative pain should be localized at an appropriate level for catheter placement in the lumbar or thoracic location of the epidural space. Patients undergoing abdominal, gynecologic, obstetric, colorectal, urologic, lower limb (e.g., major vascular), or thoracic surgery are excellent candidates for epidural pain management. Absolute contraindications to epidural analgesia include severe systemic infection or infection in the area of catheter insertion, known coagulopathy, significant thrombocytopenia, recent or anticipated thrombolytic therapy, full (therapeutic) anticoagulation, uncorrected hypovolemia, patient refusal, and anatomical abnormalities that make epidural catheter placement difficult or impossible.¹⁵⁹ T.M. is a good candidate for epidural analgesia based on the severity of pain associated with his surgery and the surgical procedure.

 

Choice of Agent and Mechanisms of Action

30. What drug or drug combination can be used for T.M.'s epidural infusion? What are the mechanisms of action of the analgesics commonly administered in the epidural space?

Opioids and local anesthetics are administered alone or in combination in epidural infusions. Opioids in the epidural space are transported by passive diffusion and the vasculature to the spinal cord, where they act at opioid receptors in the dorsal horn. After epidural administration, opioids can reach brainstem sites by cephalad movement in the cerebrospinal fluid. In addition, lipophilic opioids (fentanyl, sufentanil) have substantial systemic absorption from the epidural space.^153,160 Opioids selectively block pain transmission and have no effect on nerve transmission responsible for motor, sensory, or autonomic function.¹⁶¹ Local anesthetics, however, act on axonal nerve membranes crossing through the epidural space to produce analgesia by blocking nerve transmission. Depending on the drug, concentration, and depth of nerve penetration, local anesthetics also produce sensory, motor, or autonomic blockade (see Local Anesthetics section). Table 9-17 describes the spinal actions, efficacy, and adverse effects of opioids and local anesthetics administered by the epidural route.^{154,159,160,162}

 

Table 9-17 A Comparison of the Spinal Actions, Efficacy, and Adverse Effects of Opioids and Local Anestheticsa

Opioids Local Anesthetics Actions Site of action Substantia gelatinosa of dorsal horn of spinal cordb Spinal nerve roots Modalities blocked “Selective” block of pain conduction Blockade of sympathetic pain fibers; can cause loss of sensation and motor function Efficacy Surgical pain Partial relief Complete relief possible Labor pain Partial relief Complete relief Postoperative pain Fair/good relief Complete relief Adverse effects Nausea, vomiting, sedation, confusion, pruritus, constipation/ileus, urinary retention, respiratory depression Hypotension, urinary retention, loss of sensation, loss of motor function resulting in inability to ambulate aEpidurally administered morphine and local anesthetics exert their effects mainly by a spinal mechanism of action; lipophilic opioids such as fentanyl and sufentanil achieve therapeutic plasma concentrations when administered epidurally. bAnd/or other sites where opioid receptor-binding sites are present. Adapted from references 154, 159, 160, and 162.

Most often, opioids and local anesthetics are combined in the same solution because these two classes of drugs act synergistically at two different sites to produce analgesia, allowing the administration of lower doses of each drug to reduce the risk of adverse effects while providing effective analgesia. Table 9-18 lists the drugs, concentrations, and typical infusion rates for epidural administration.^{155,156,160,161,163} Bupivacaine is commonly chosen as the local anesthetic agent because it can preferentially block sensory fibers (producing analgesia) without significantly blocking motor fibers.¹⁵⁵ The choice of opioid is based on pharmacokinetic differences among the available agents. Onset, duration, spread of agent in the spinal fluid (dermatomal spread), and systemic absorption are affected by the lipophilicity of the drug.¹⁶² Highly lipophilic opioids such as fentanyl and sufentanil have a faster onset of action, a shorter duration of action (from a single dose), less dermatomal spread, and much greater systemic absorption. Morphine, which is relatively hydrophilic, has a slower onset of action, longer duration of action, greater dermatomal spread and migration to the brain, and less systemic absorption.^160,162 However, after several hours of epidural infusion, the dermatomal (regional) effect of fentanyl is lost, and analgesia is achieved because of a therapeutic plasma concentration. Morphine, however, retains its spinal mechanism of action.¹⁶⁰ The lipophilicity of hydromorphone is intermediate between fentanyl and morphine. Clinically, hydromorphone has a faster onset and shorter duration than morphine. Its site of action is likely spinal.¹⁶⁴ A

P.9p31

comparison of the pharmacokinetic properties important to epidural opioids is found in Table 9-19.^{155,158,162,163} T.M. should receive a combination of opioid and local anesthetic, such as fentanyl and bupivacaine, as an epidural infusion for postoperative pain management.

Table 9-18 Adult Analgesic Dosing Recommendations for Epidural Infusion

Drug Combinations or Druga Infusion Concentrationb Usual Infusion Rateb Morphine + bupivacaine 25–100 µg/mL (M) 4–10 mL/hr   0.5–1.25 mg/mL (B)   Hydromorphone + bupivacaine 3–20 µg/mL (H) 4–10 mL/hr   0.5–1.25 mg/mL (B)   Fentanyl + bupivacaine 2–10 µg/mL (F) 4–10 mL/hr   0.5–1.25 mg/mL (B)   Sufentanil + bupivacaine 1 µg/mL (S) 4–10 mL/hr   0.5–1.25 mg/mL (B)   Morphine 100 µg/mL 5–8 mL/hr aUse only preservative-free products and preservative-free 0.9% sodium chloride as the admixture solution. bExact concentrations and rates are institution specific. Initial concentration and/or rate often depend on the age and general condition of the patient. M, morphine; B, bupivacaine; H, hydromorphone; F, fentanyl; S, sufentanil. Adapted from references 155, 156, 160, 161, and 163.

 

31. Fentanyl/bupivacaine is chosen for T.M. How should this be prepared, and what infusion rate should be chosen?

Fentanyl and bupivacaine are commonly admixed in 0.9% sodium chloride (usual concentration ranges are found in Table 9-18). Concentrations are often institution specific and depend on the rate of administration. Preservative-free preparations of each drug should be used because neurologic effects are possible with inadvertent subdural administration of large amounts of benzyl alcohol or other preservatives. Strict aseptic technique should be used when admixing and administering an epidural solution.

The rate of administration is chosen empirically based on the anticipated analgesic response, the concentration of opioid in the admixture, and the potential for adverse effects. Usually, a rate of 4 to 10 mL/hour is adequate; the epidural space can safely handle up to approximately 20 mL/hour of fluid. An initial infusion rate of 5 to 8 mL/hour would be reasonable for T.M., with titration based on efficacy and adverse effects.

 

Adverse Effects

32. Two hours after initiation of his fentanyl/bupivacaine epidural infusion, T.M. experiences discomfort in the form of an itchy feeling on his nose, torso, and limbs. Is this related to his epidural infusion?

Table 9-19 Pharmacokinetic Comparison of Common Epidural Opioid Analgesics

Agent Partition Coefficienta Onset of Action of Bolus (minutes) Duration of Action of Bolus (hours) Dermatomal Spread Fentanyl (Sublimaze) 955 5 3–6 Narrow Hydromorphone (Dilaudid) 525 15 6–17 Intermediate Morphine Sulfate (Duramorph) 1 30 12–24 Wide Sufentanil (Sufenta) 1,737 5 4–7 Narrow aOctanol/water partition coefficient; used to assess lipophilicity; higher numbers indicate greater lipophilicity. Adapted from references 155, 158, 162, and 163.

 

Pruritus has been associated with almost all opioids, with a significantly greater frequency when the opioid is administered as an epidural infusion rather than by IV administration.¹⁶⁵ This effect is usually seen within 2 hours and is probably dose related. It generally subsides as the opioid effect wears off and can be more of a problem with continuous epidural administration of opioids or when opioids are administered via PCA. Although pruritus from opioids is probably µ-receptor mediated and not histamine mediated,¹⁶⁶ antihistamines (e.g., diphenhydramine) can provide symptomatic relief. Alternatively, very small doses of opioid antagonists (e.g., naloxone 0.04 mg) can be used to effectively reverse opioid adverse effects, such as pruritus, but not analgesia. Due to naloxone's short duration of action, repeat doses or a continuous infusion may be necessary.

Other adverse effects possible with epidural opioids include nausea, vomiting, sedation, confusion, constipation, ileus, urinary retention, and respiratory depression. Although rare, respiratory depression from epidural opioids is the most dangerous adverse effect. Respiratory depression can occur as long as 12 to 24 hours after a single bolus of morphine^160,162 or within hours to 6 days after beginning a continuous infusion of fentanyl/bupivacaine.¹⁶⁷ Typically, regular assessments of sedation level and rate and depth of respirations safely detect respiratory depression from opioids.^148,160 As with parenteral opioid administration, risk factors for opioid-related respiratory depression include severe underlying systemic disease or pre-existing respiratory compromise, concomitant use of other sedative-hypnotics (e.g., benzodiazepines, opioids administered by another route), and older age. As a result, reduced doses should be used in patients with these risk factors. Adverse effects of epidural local anesthetics include hypotension, urinary retention, lower limb paresthesias or numbness, and lower limb motor block. Depending on the degree of numbness and motor block, the patient may have difficulty ambulating. Monitoring for efficacy and adverse effects of epidural analgesia should include pain intensity and quality, response to treatment, number of on-demand requests (if PCA is being used), analgesic consumption, BP, heart rate, respiratory depth and rate, level of sedation, urinary output, presence of numbness/tingling, inability to raise legs or flex knees/ankles (lumbar epidural placement), and temperature.

 

Adjunctive Ketorolac Use

33. On the second postoperative day, T.M. is able to rest comfortably when undisturbed, while receiving treatment with a lumbar epidural infusion of fentanyl 3 µg/mL and bupivacaine 1.25 mg/mL at a rate of 8 mL/hour. However, when he is moved at the change of each nursing shift, he complains of significant pain. Increasing the rate of his epidural infusion was tried, but caused unacceptable pruritus and sedation. How can T.M.'s intermittent pain needs be addressed?

The use of additional analgesics for breakthrough pain may be necessary in patients receiving continuous epidural infusion. T.M.'s intermittent pain could be managed by patient-controlled epidural analgesia. Like IV PCA, patient-activated epidural boluses can be administered to control pain during movement. Alternatively, ketorolac, an injectable NSAID, may be considered for T.M.; it does not contribute to respiratory depression, sedation, or pruritus and effectively treats moderate-to-severe pain. The analgesic effects of NSAIDs are additive with the opioids and can lower postoperative pain scores. Patient selection for ketorolac therapy should consider renal function, plasma volume and electrolyte status, GI disease, risk of bleeding, and concomitant drugs and therapies such as epidural analgesia.

 

Adjunctive Anticoagulant Administration

34. The surgeon has determined that T.M. is at risk for developing postoperative venous thromboembolism. Enoxaparin 40 mg SC QD has been ordered postoperatively. What are the risks of enoxaparin in this situation? What are reasonable precautions?

Prolonged therapeutic anticoagulation appears to increase the risk of epidural and spinal hematoma formation, which can lead to long-term or permanent paralysis. Administration of antiplatelet or anticoagulant drugs in combination with low-molecular-weight heparin (LMWH) results in an even greater risk of perioperative hemorrhagic complications, including spinal hematoma. These findings have led to concern for the safety of spinal and epidural anesthesia and analgesia in patients receiving LMWH. Important considerations for managing a patient being administered LMWH and receiving continuous epidural analgesia are (a) the time of catheter placement and removal relative to the timing (and peak effect) of LMWH administration, (b) total daily dose of LMWH, and (c) the dosing schedule of LMWH.¹⁶⁸ For T.M., the epidural catheter is already in place and the LMWH is started postoperatively as a single daily dose. It is safe to leave the epidural catheter in place as long as the first dose of LMWH is administered 6 to 8 hours postoperatively. The second dose should be administered no sooner than 24 hours after the first dose. The timing of the catheter removal is of the utmost importance; it should be delayed for at least 10 to 12 hr after the last dose of LMWH, with subsequent dosing occurring a minimum of 2 hours after the catheter has been removed. There may be a greater risk of spinal hematoma when LMWH is administered twice a day. For that reason, if Q 12 hr enoxaparin is required, the catheter should be removed, and the first dose of LMWH administered at least 2 hours after catheter removal.¹⁶⁸ Because T.M. is receiving prophylactic daily enoxaparin, his catheter should be removed no earlier than 10 hours after his last dose of enoxaparin, with his next dose administered no earlier than 2 hours after catheter removal.

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Patient-Controlled Analgesia

Patient-Controlled Analgesia

Advantages

22. J.A., a 50-year-old, 5′4′′, 50-kg woman, is immediately postoperative from a total abdominal hysterectomy for a neoplasm. Her laboratory values are remarkable for a SrCr of 1.3 mg/dL (normal, 0.6–1.0 mg/dL). She is allergic to penicillin. She will be admitted to the postsurgical floor for a planned stay of 2 to 3 days. What mode of pain management should be chosen for J.A.?

PCA is a popular method of administering analgesics and offers several advantages over traditional IM or IV opioid dosing. Patients treated with intermittent IM or IV dosing of opioids “as needed” can experience severe pain because the serum opioid concentration is allowed to fall to less than the minimum effective analgesic concentration (the concentration that provides approximately 90% pain relief). In addition, high peak plasma opioid concentrations can be seen with this administration method, often resulting in excessive nausea, vomiting, or sedation, as well as respiratory depression. Small, frequent opioid doses, as seen in PCA, minimize the peaks and valleys in serum concentrations seen with relatively larger intermittent IM or IV doses. This is helpful in avoiding adverse effects associated with high peak serum concentrations and inadequate pain relief caused by subtherapeutic serum concentrations. Small, frequent, patient-controlled dosing of opioids is efficacious because opioids have a steep sigmoidal dose–response curve for analgesia, resulting in the ability of a small opioid dose to move the plasma concentration from being subtherapeutic to above the minimum effective plasma concentration that will provide effective pain relief.^147,148 In terms of safety, analgesia occurs at lower opioid dosages than sedation, and sedation generally precedes respiratory depression.¹⁴⁹ Therefore, if a patient becomes sedated, self-administration of additional patient-controlled bolus doses will stop, allowing the serum opioid concentration to fall to a safe level.

 

Therapy can be individualized by using small doses of opioids at preset intervals (e.g., 1 mg morphine every 8 minutes), with the patient in control of his or her analgesic administration. An infusion pump, with a programmed on-demand dose (the dose the patient can self-administer) and number of minutes between allowable doses (lock-out interval), is equipped with a button that the patient presses to receive a dose. IV bolus is the most common PCA route, with opioids being the drugs of choice to provide postoperative analgesia. The epidural route can also be used in select patients.

If the patient is educated to use PCA properly, it can be used to alleviate anticipated pain before movement or physical therapy in a pre-emptive fashion. J.A. has undergone a procedure for which moderate-to-severe pain is expected in the immediate postoperative period. J.A.'s pain requirement in the immediate postoperative period could be met with PCA opioid administration after first administering a bolus dose of opioid, which is titrated to achieve the appropriate level of analgesia. When her opioid requirements decline or when she can tolerate oral intake, she can then be switched to oral analgesics.

Patient Selection

23. J.A.'s surgeon decides to prescribe PCA for postoperative pain management. How should J.A. be evaluated for her ability to appropriately participate in her analgesic administration?

Patients receiving PCA therapy must be able to understand the concept behind PCA and to operate the drug administration button. J.A. must be alert and oriented before being put in control of her own pain management. She must be able to comprehend verbal and/or written instructions regarding the function and safety features of the infusion pump and how to titrate drug as needed for satisfactory analgesia. PCA has been used successfully in children, generally after ages 8 or 9 (adjusting doses appropriately) and in elderly patients. PCA is not indicated in patients who are expected to require parenteral opioids for analgesia for <24 hours because these patients will generally be able to tolerate oral analgesics shortly after surgery.

 

Patient Instructions

24. J.A. is nervous about giving herself an overdose while using PCA. What instructions should be provided to her?

Patients often worry about the safety of PCA, which can lead to reluctance to provide themselves with adequate pain relief. J.A. should be informed that if she administers too large of an amount of the prescribed opioid analgesic, she should fall asleep. Because she is asleep, she will not press the button. When this adverse effect of the opioid has worn off, she will wake up (plasma opioid level has fallen back into or below the therapeutic range). This is an important safety feature of PCA and is the reason family members must not push the button for the patient. However, J.A. should also know that she may have to press the button several times (after the lock-out interval has passed) before her pain is relieved. She must also be informed that she may require a larger PCA dose, so it is important for J.A. to assess her pain relief from the “usual” dose most patients are initially started on following surgery. Accurate pain assessment following her prescribed dose is critical for ensuring that her dose is sufficient to provide the desired level of analgesia. She should also understand the possible adverse effects of her PCA medication and what can be done to prevent and treat these effects, as well as the advantages of providing herself with adequate analgesia (e.g., early ambulation). Finally, she should be told of the negligible risk of “narcotic” addiction from short-term PCA use and be given ample opportunity to ask questions.

 

Choice of Agent

25. Meperidine is ordered for J.A.'s PCA. Is this a reasonable drug choice for her?

Ideally, opioids for PCA administration have a rapid onset and intermediate duration of action (30-60 minutes), with no accumulation, ceiling effect, or adverse effects. The physicians, nurses, and pharmacists involved with the care of the patient should be familiar with the drug selected for PCA. Morphine is by far the most common choice for PCA, although other opioids such as fentanyl and hydromorphone can be used. Drug choice is based on past patient experiences, allergies, adverse effects, and special considerations, such as renal function. Meperidine has a metabolite, normeperidine, which is renally excreted; has a long half-life; and can cause cerebral irritation and excitation. Symptoms of CNS toxicity from normeperidine include agitation, shaky feelings, delirium, twitching, tremors, and myoclonus/tonic-clonic seizures. These symptoms can be seen when meperidine is administered in higher doses and/or for a prolonged period.^150,151 The presence of renal insufficiency increases the risk of accumulation of normeperidine.¹⁵⁰ Meperidine also inhibits serotonin reuptake and has a fairly high serotonergic potential. The risk of a patient developing the serotonin syndrome is greater when meperidine is coadministered with another drug that has moderate or high serotonergic potential (e.g., fluoxetine, fluvoxamine, paroxetine, venlafaxine).¹⁵² For these reasons, meperidine is a poor choice for analgesia, particularly for J.A. who has diminished renal function. Morphine is conjugated with glucuronide in hepatic and extrahepatic sites (particularly the kidney) to its two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide; both metabolites are excreted primarily in the urine. Morphine-6-glucuronide is an active metabolite that can accumulate in patients with renal failure, resulting in prolonged analgesia, sedation, and respiratory depression.¹⁵³ Because of J.A.'s diminished renal function, morphine should probably be avoided because other options exist. Hydromorphone is not metabolized to an active 6-glucuronide metabolite, and fentanyl is metabolized to inactive metabolites. Either hydromorphone or fentanyl is an appropriate analgesic choice for J.A. Hydromorphone is chosen. Table 9-16 lists common doses and lock-out intervals for drugs administered by PCA.^154,155,156

 

Dosing

26. J.A. was not receiving an opioid prior to surgery (e.g., she is opioid naive). What dose of hydromorphone and what lock-out interval should be used for her initial PCA pump settings?

If J.A. is experiencing pain before PCA has been initiated, she should receive a loading dose of IV hydromorphone titrated to achieve baseline pain relief (usually up to 1 mg). Once adequate analgesia is achieved, demand doses of 0.2 mg with a lock-out interval of 8 minutes would be a good choice to maintain analgesia for this opioid-naive patient. If J.A.'s pain is not relieved after two to three demand doses within 1 hour, the demand dose can be increased to 0.3 mg.

Table 9-16 Adult Analgesic Dosing Recommendations for Intravenous Patient-Controlled Analgesiaa

Drug Usual Concentration Demand Dose (mg) Lock-Out Interval (min) Usual Range Fentanyl (as citrate) (Sublimaze) 10 µg/mL 0.01–0.02 0.01–0.05 4–8 Hydromorphone hydrochloride (Dilaudid) 0.2 mg/mL 0.2–0.3 0.1–0.5 5–10 Morphine sulfate 1 mg/mL 1–2 0.5–3 5–10 aAnalgesic doses are based on those required by a healthy 55- to 70-kg, opioid-naive adult. Analgesic requirements vary widely between patients. Doses may need to be adjusted because of age, condition of the patient, and prior opioid use. Adapted from references 154, 155, 156.

 

Use of a Basal Infusion

 

 

Many PCA infusion pumps offer a continuous infusion setting for a basal infusion during intermittent dosing. Use of a basal (continuous) infusion has not been shown to improve analgesia and likely increases the risk of adverse effects (due to the potential of an opioid overdose in some patients). Therefore, routine basal (continuous) infusion of opioids cannot be recommended for acute pain management. In an opioid-naïve patient such as J.A., however, continuing to increase the demand dose increases the risk of excessive sedation and respiratory depression (due to high peak levels). Also, J.A. describes her pain as moderate to severe in intensity and fairly constant in nature when she does not regularly push the demand button. For J.A., a continuous infusion would be beneficial. As a rule of thumb, an opioid-naïve patient experiencing acute pain (that can change quickly) should only receive about one-third of her average hourly usage as a continuous infusion or 1 mg/hour of morphine (or its equivalent, which would be 0.2 mg/hour for hydromorphone). For J.A., begin a continuous infusion of 0.2 mg/hour hydromorphone in addition to her demand dose of 0.3 mg every 8 minutes. Because the onset of action of hydromorphone is about 5 minutes, shortening the lock-out interval is not a good idea because J.A. could access the next dose of hydromorphone before the effects of the initial dose can be appreciated. That could lead to significant adverse effects, such as excessive sedation and respiratory depression.

 

Adverse Effects

28. The next day, J.A. requested only a few demand doses and reports adequate pain relief with her PCA, but now complains of feeling slightly groggy and nauseated. Bowel sounds are noted on physical examination, and J.A. plans to try to take clear liquids later that morning. What are the adverse effects of PCA opioids, and how can J.A.'s complaints be addressed?

Opioids given by PCA can produce adverse effects similar to those given by other parenteral routes. Sedation, confusion, euphoria, nausea and vomiting, constipation, urinary retention, and pruritus can be experienced, and these can be managed by dose adjustments or pharmacologic intervention. Respiratory depression is very rare with PCA opioid administration.¹⁵⁵ However, elderly patients, patients with severe underlying systemic disease or pre-existing respiratory compromise, and those who are receiving other sedative-hypnotics concomitantly are predisposed to respiratory depression.¹⁴⁸ Technical problems must also be ruled out. The PCA pump should be checked to ensure that it is delivering the correct drug and dose, programming should be checked for accuracy (e.g., drug concentration, dosing interval), and the opioid reversal agent naloxone must be readily available. Monitoring for efficacy and adverse effects of PCA therapy should include pain intensity and quality, response to treatment, number of on-demand requests, analgesic consumption, BP, heart rate, respiratory rate, and level of sedation, as well as the presence of other adverse effects of opioids such as nausea and itching.

 

J.A.'s PCA hydromorphone dose could be reduced to manage her sedation and nausea. However, her pain control must be carefully reassessed to ensure efficacy of the newly lowered dose. An order for an antiemetic could also be provided. NSAIDs (ketorolac IM/IV or other NSAID orally) are not sedating; thus, they could be added to the analgesic regimen to provide analgesia and allow a reduction in her opioid dose. However, because of J.A.'s compromised renal function, NSAIDs should be administered with caution and in lower doses (e.g., 15 mg IM/IV ketorolac). Before administering ketorolac, J.A.'s hydration status should be evaluated to ensure that she is not hypovolemic.¹⁵⁷ If J.A. is able to take fluids orally, PCA should be discontinued and oral analgesics administered as needed. As healing occurs, her pain intensity should lessen, and oral opioid/acetaminophen products should manage her pain adequately.

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Antiemetic Agents and Postoperative Nausea and Vomiting

Antiemetic Agents and Postoperative Nausea and Vomiting

Impact of Postoperative Nausea and Vomiting

PONV is a relatively common (overall incidence, 25%-30%) yet highly undesirable anesthetic and surgical outcome. Patients who develop PONV are greatly dissatisfied with their surgical experience and require additional resources such as nursing time and medical/surgical supplies. PONV typically lasts <24 hours; however, symptom distress can continue at home, thereby preventing the patient from resuming normal activities or returning to work.¹¹⁹ It is important to remember that nausea is a separate subjective sensation and is not always followed by vomiting. Nausea can be as or more distressing to patients as vomiting.

Mechanisms of and Factors Affecting Postoperative Nausea and Vomiting

The vomiting center is reflex activated through the chemoreceptor trigger zone (CTZ). Input from other sources can also stimulate the vomiting center. Afferent impulses from the periphery (e.g., manipulation of the oropharynx or GI tract), the cerebral cortex (e.g., unpleasant tastes, sights, smells, emotions, hypotension, pain), and the endocrine environment (e.g., female gender) can also stimulate the vomiting center. In addition, disturbances in vestibular function (e.g., movement after surgery, middle ear surgery) can stimulate the vomiting center via direct central pathways and the CTZ. Neurotransmitter receptors that play an important role in impulse transmission to the vomiting center include dopamine type 2 (D₂), serotonin (5HT₃), muscarinic cholinergic (M₁), histamine type 1 (H₁), and neurokinin type 1 (NK₁) (Fig. 9-1).^{119,120,121,122,123,124,125} The vestibular apparatus is rich in M₁ and H₁ receptors. Opioid analgesics can activate the CTZ, as well as the vestibular apparatus, to produce nausea and vomiting.^{119,120,121,122}

PONV is probably not caused by a single event, entity, or mechanism; instead, the cause is likely to be multifactorial. Factors that place a patient at risk for developing PONV in adults include female gender, history of PONV and/or motion sickness, nonsmoking status, use of opioids, type of surgery, duration of surgery, and general anesthesia with inhalation anesthetic agents and/or nitrous oxide.¹²⁶ For children, risk factors for postoperative vomiting include duration of surgery ≥30 minutes, age ≥3 years, strabismus surgery, and a history of postoperative vomiting in the child or PONV in the mother, father, or siblings.¹²⁵ Unlike adults, nausea is not easily measured in children and hence not routinely assessed.

18. J.E., a 34-year-old, 55-kg woman, is scheduled to undergo a gynecologic laparoscopy under general anesthesia on an outpatient basis. She has had one previous surgery, has no known medication allergies, and is a nonsmoker. On questioning, she reports that she developed PONV following her first surgery. Her physical examination is unremarkable. Is J.E. a candidate for prophylactic antiemetic therapy?

J.E. has several risk factors that make her susceptible to developing PONV. Adult women are two to three times more likely than adult men to develop PONV. Previous PONV also increases the likelihood of developing PONV threefold. In addition, a nonsmoking status increases the risk of developing PONV. The type of procedure J.E. is undergoing (gynecologic laparoscopy) places her at a higher risk for developing PONV. Finally, J.E. is scheduled for general anesthesia, which is also associated with a greater risk of PONV when compared with regional anesthesia. Because of the presence of many risk factors, J.E. is at high risk and should be administered at least two prophylactic antiemetic agents. Patients undergoing surgery view PONV as a highly undesirable consequence, thereby reducing their overall level of satisfaction.

Figure 9-1 Mechanisms and neurotransmitters of postoperative nausea and vomiting. The chemoreceptor trigger zone (CTZ) is located in the area postrema of the midbrain. The vomiting center is also located in the midbrain, close to the nucleus tractus solaritus (NTS) and the area postrema. The CTZ, NTS, and area postrema are rich in 5-HT3, H1, M1, D2, and µ-opioid receptors. Antiemetic agents used to manage postoperative nausea and vomiting block one or more of these receptors. D2, dopamine type 2 receptor; 5-HT3, serotonin type 3 receptor; M1, muscarinic cholinergic type 1 receptor; NK1, neurokinin type 1 receptor; H1, histamine type 1 receptor; GI, gastrointestinal; ICP, intracranial pressure; CSF, cerebral spinal fluid. Source: Adapted from references 119, 120, 121, 122, 123, 124, 125.

Prevention of Postoperative Nausea and Vomiting: Choice of Agent

19. Which antiemetic drugs would be most appropriate for J.E., and when should they be administered?

Antiemetic drugs can be classified as antimuscarinics (scopolamine, promethazine, diphenhydramine), serotonin antagonists (ondansetron, dolasetron, granisetron), benzamides (metoclopramide), butyrophenones (droperidol), phenothiazines (prochlorperazine), and the NK₁ antagonist, aprepitant. These drugs exert their antiemetic effects primarily by blocking one central neurotransmitter receptor. Dopamine antagonists include the benzamides, butyrophenones, and phenothiazines. Ondansetron, granisetron, and dolasetron block 5HT₃ receptors of vagal afferent nerves in the GI tract and in the CTZ. Antimuscarinics likely exert their antiemetic effect by blocking Ach in the vestibular apparatus, vomiting center, and CTZ. The proposed site of action, usual adult dose, and select adverse effects of the commonly used antiemetic drugs for prevention and treatment of PONV are summarized in Table 9-15.^{3,119,121,125-127}

Butyrophenones

Droperidol possesses significant antiemetic activity, with IV doses of 0.625 to 1.25 mg effectively preventing PONV. Droperidol is more effective for nausea than vomiting, even at a dose as low as 0.3 mg. Droperidol has an onset of action of 3 to 10 minutes, with peak effects seen at 30 minutes. Doses of 0.625 or 1.25 mg often prevent PONV for up to 24 hours.

 

The duration of action of a 0.3-mg dose, however, is short lived, with repeated doses often necessary. Droperidol is most effective when administered near the end of surgery. Adverse effects include sedation (especially at doses ≥2.5 mg), anxiety, hypotension, and, rarely, restlessness or other extrapyramidal (EP) reactions.¹²⁸ Because of its effectiveness and cost, droperidol has historically been used extensively as a first-line agent. However, in December 2001, the FDA strengthened warnings regarding adverse cardiac events following droperidol administration. With the new warning to perform continuous 12-lead electrocardiographic monitoring before and for 2 to 3 hours following administration of droperidol, it became an issue, from both expense and logistical viewpoints, to administer droperidol to an outpatient, patient in the PACU (recovery room), or patient in an unmonitored bed. Because low-dose droperidol has been used for >30 years to prevent PONV, many anesthesia providers challenged the decision of the FDA to issue this “black box” warning.¹²⁹ Nuttall et al.¹³⁰ retrospectively examined whether low-dose droperidol 

administration increased the incidence of torsades de pointes (TdP) in patients undergoing general surgery. Of the 16,791 patients exposed to droperidol, no patient experienced TdP. The authors concluded that the FDA's black box warning for low-dose droperidol is excessive and unnecessary.

Table 9-15 Classification, Proposed Site(s) of Action, Usual Dose, and Adverse Effects of Select Antiemetic Drugs

Antiemetic Drug Proposed Receptor Site of Action Usual Dosea Duration of Action Adverse Effects Comments Butyrophenones Droperidol (Inapsine) D2 Adult: 0.625–1.25 mg IV Pediatric: 20–50 µg/kg IV for prevention; 10-20 mcg/kg IV for treatment ≤12–24 hr Sedation, dizziness, anxiety, hypotension (especially in hypovolemic patients), EPS Monitor ECG for QT prolongation/torsades de pointes Phenothiazines Prochlorperazine (Compazine) D2 Adult: 5–10 mg IM or IV; 25 mg PR Pediatricb: 0.1-0.15 mg/kg IM, 0.1–0.13 mg/kg PO, 2.5 mg PR 4–6 hr (12 hr when given PR) Sedation, hypotension (especially in hypovolemic patients), EPS   Antimuscarinics Promethazine (Phenergan) D2, H1, M1 Adult: 6.25–25 mg IM, IV, or PRc 4-6 hr Sedation, hypotension (especially in hypovolemic patients), EPS, serious tissue injury from inadvertent arterial injection or IV extravasation Limit concentration to 25 mg/mL; dilute in 10-20 mL saline, inject through a running line, and advise patient to report IV site discomfort Diphenhydramine (Benadryl) H1, M1 Adult: 12.5–50 mg IM or IV 4–6 hr Sedation, dry mouth, blurred vision, urinary retention       Pediatric: 1 mg/kg IV, PO (max: 25 mg for children younger than 12 years)       Scopolamine (Transderm Scop) M1 Adult: 1.5 mg transdermal patch 72 hrd Sedation, dry mouth, visual disturbances, dysphoria, confusion, disorientation, hallucinations Apply at least 4 hr before end of surgery; wash hands after handling patch; not appropriate for children, elderly, or patients with renal/hepatic impairment Benzamides Metoclopramide (Reglan) D2 Adult: 10-20 mg IV Pediatric: 0.25 mg/kg IV ≤6 hr Sedation, hypotension, EPS Consider for rescue if N/V is believed to be due to gastric stasis; reduce dose to 5 mg in renal impairment; give slow IV push Serotonin Antagonists Ondansetron (Zofran) 5-HT3 Adult: 4 mg IV Up to 24 hr Headache, lightheadedness, QT prolongation       Pediatric: 0.05–0.1 mg/kg IV       Dolasetron (Anzemet) 5-HT3 Adult: 12.5 mg IV Up to 24 hr Headache, lightheadedness, QT prolongation       Pediatric: 0.35 mg/kg IV       Granisetron (Kytril) 5-HT3 Adult: 0.35 mg-1 mg IV Pediatric: Not known Up to 24 hr Headache, lightheadedness, QT prolongation   Palonosetron (Aloxi)   Adult: 0.075 mg IV Up to 24 hr Bradychardia, headache, QT prolongation   NK1 Antagonists Aprepitant (Emend) NK1 Adult: 40 mg PO up to 3 hr before surgery Up to 24 hr Headache   Other Dexamethasone (Decadron) None Adult: 4–8 mg IV Pediatric: 0.15 mg/kg IV Up to 24 hr Genital itching, flushing, hyperglycemia   aUnless otherwise indicated, pediatric doses should not exceed adult doses. bChildren >10 kg or older than 2 years only. Change from IM to PO as soon as possible. When administering PR, the dosing interval varies from 8 to 24 hours, depending on the child's weight. cMaximum of 12.5 mg in children younger than 12 years. dRemove after 24 hours. Instruct patient to thoroughly wash the patch site and their hands. 5-HT3, serotonin type 3 receptor; D2, dopamine type 2 receptor; ECG, electrocardiogram; EPS, extrapyramidal symptoms (e.g., motor restlessness or acute dystonia); H1, histamine type 1 receptor; IV, intravenous; IM, intramuscular; M1, muscarinic cholinergic type 1; N/A, not applicable; N/V, nausea and/or vomiting; PO, orally (by mouth); PR, per rectum. Adapted from references 3, 119, 121, and 125, 126, 127.

Benzamides

Metoclopramide, in doses of 10 to 20 mg, has been used in the prevention and treatment of PONV. However, variable results have been seen with this agent.¹³¹ For maximum benefit, metoclopramide must be administered near the end of surgery (secondary to its rapid redistribution after IV administration); 10 mg IV administered at the beginning of surgery is not effective. Adverse effects of metoclopramide include drowsiness and EP reactions, such as anxiety and restlessness. Metoclopramide should be administered by slow intravenous injection over at least 2 minutes to minimize the risk of EP reactions and cardiovascular effects such as hypotension, bradycardia, and supraventricular tachycardia.

Serotonin Antagonists

Ondansetron (4 mg IV) was the first 5HT₃ antagonist to receive an indication for PONV. Dolasetron (12.5 mg IV) and granisetron (1 mg IV) are also approved for preventing and treating PONV. Palonosetron (0.075 mg IV) is approved for the prevention of PONV for up to 24 hours following surgery. As a general rule, serotonin antagonists are consistently more effective in reducing vomiting rather than nausea.¹³² Ondansetron and dolasetron are equally efficacious in preventing PONV.¹³³ A single dose of ondansetron, dolasetron, or granisetron provides acute relief and can protect against nausea and vomiting for up to 24 hours after administration. For optimal efficacy, serotonin antagonists should be administered near the end of surgery. Adverse effects are minimal and include headache, constipation, and elevated liver enzymes. Because of their good efficacy and adverse effect profile, serotonin antagonists are recommended as first-line therapy.¹²⁵

Dexamethasone

Dexamethasone is frequently used as an antiemetic in patients undergoing highly emetogenic chemotherapy. Its mechanism of action as an antiemetic is not well understood, particularly in the surgical setting. When compared to placebo, a prophylactic dose of dexamethasone is antiemetic in high-risk patients. It is most effective in preventing late PONV (up to 24 hours). Adverse effects in otherwise healthy patients are minimal and include headache, dizziness, drowsiness, constipation, and muscle pain.¹³⁴ Because of its good efficacy and adverse effect profile (from a single dose), dexamethasone is also recommended as first-line therapy.¹²⁵ Unlike droperidol and the serotonin antagonists, dexamethasone is most effective when administered at the beginning of surgery (immediately before induction).¹³⁵

Phenothiazines

Prochlorperazine has been used successfully to prevent PONV. Prochlorperazine (10 mg IM) was found to have superior efficacy (less nausea and vomiting, as well as less need for rescue antiemetics) when compared with ondansetron for preventing PONV.¹³⁶ Prochlorperazine may cause sedation, EP reactions, and cardiovascular effects. Because it has a short duration of action, multiple doses may be necessary.

Antimuscarinics

Scopolamine blocks afferent impulses at the vomiting center and blocks Ach in the vestibular apparatus and CTZ.
Transdermal scopolamine is useful for prevention of nausea, vomiting, and motion sickness. Compared with placebo, transdermal scopolamine effectively reduces the incidence of emetic symptoms.¹³⁷ Common side effects include dry mouth and visual disturbances. Patients can also have trouble correctly applying the patch. It is important to apply the patch before surgery because its onset of effect is 4 hours. Patients should also be instructed to wash their hands after applying the patch and to dispose of the patch properly.

Neurokinin-1 Antagonists

Aprepitant is the first NK₁ antagonist to be approved for prevention of PONV. Aprepitant has a long half-life and is administered orally prior to surgery. For prevention of PONV in patients undergoing abdominal surgery, aprepitant was similar in efficacy (defined as no vomiting and no use of rescue antiemetics in the first 24 hours following surgery) to ondansetron. Aprepitant, however, was significantly more effective than ondansetron in preventing vomiting at 24 and 48 hours after surgery. Aprepitant was well tolerated, with adverse effects similar to ondansetron.¹³⁸

Combination of Agents

As discussed, droperidol, serotonin antagonists, dexamethasone, and transdermal scopolamine effectively prevent PONV. However, these agents fail to prevent PONV in approximately 20% to 30% of patients. Most of the agents effectively block one receptor believed to be involved in the activation of the vomiting center. However, because the cause of PONV is likely multifactorial, a combination of antiemetic agents (from different classes) is more efficacious for preventing PONV in a high-risk patient. In a factorial trial of six interventions for prevention of PONV in more than 5,000 high-risk patients undergoing surgery, patients were randomly assigned to 1 of 64 possible combinations of six different prophylactic interventions: 4 mg IV ondansetron or no ondansetron; 4 mg IV dexamethasone or no dexamethasone; 1.25 mg IV droperidol or no droperidol; propofol or a volatile inhalation anesthetic agent; nitrous oxide or nitrogen (i.e., no nitrous oxide); and remifentanil (an ultrashort-acting opioid) or fentanyl (a short-acting opioid).¹³⁹ Each antiemetic agent intervention (ondansetron, dexamethasone, droperidol) had similar efficacy and reduced the risk of PONV by about 26%. The risk was further reduced when a combination of any two antiemetics was administered, with no difference between the various combinations of agents. The risk was the lowest when all three antiemetic agents were administered.

For prophylaxis of PONV, J.E. should receive at least two antiemetic agents because she is at high risk for developing PONV. Dexamethasone 4 mg IV can be administered at the beginning of surgery (just after induction of anesthesia) and 4 mg IV ondansetron should be administered approximately 30 minutes before the end of surgery. If an alternative agent (to ondansetron and dexamethasone) or third agent is warranted, a transdermal scopolamine patch can be placed within 2 hours before the induction of general anesthesia. The addition of transdermal scopolamine to ondansetron for prevention of PONV significantly reduces PONV, as well as supplemental antiemetic requirements.¹⁴⁰

Treatment of Postoperative Nausea and Vomiting

20. J.E. is taken to surgery. Anesthesia is induced with propofol and maintained with sevoflurane. Fentanyl is administered intraoperatively for analgesia. A prophylactic dose of dexamethasone is administered at the beginning of surgery, and ondansetron is administered near the end of surgery. Neuromuscular blockade produced by vecuronium is reversed with neostigmine and glycopyrrolate. In the recovery room, J.D. becomes nauseated and has several emetic episodes. What do you recommend?

Although dexamethasone and ondansetron are effective for both prevention and treatment of PONV, a rescue antiemetic is more efficacious if it works by a different mechanism of action.¹⁴¹ Prophylactic dexamethasone and/or ondansetron can be effective for up to 24 hours. If nausea and emetic episodes occur in the recovery room, the prophylactic antiemetic agents were ineffective. Phenothiazines (prochlorperazine) and benzamides (metoclopramide) block dopaminergic stimulation of the CTZ, making these agents appropriate for J.E. Prochlorperazine may be preferred because metoclopramide's primary effect is in the GI tract rather than the CTZ. Diphenhydramine or promethazine, which blocks Ach receptors in the vestibular apparatus, as well as histamine receptors that activate the CTZ, would also be appropriate choices for rescue for J.E. Because excessive sedation could delay J.E.'s discharge from the ambulatory surgery center, doses should not exceed 25 mg IV for promethazine and 50 mg IV for diphenhydramine. In addition, it is important to assess J.E. for postoperative factors that could increase the likelihood of PONV. If postural hypotension is present, IV fluids and ephedrine would be appropriate therapy. Postoperative pain must also be assessed because PONV is directly related to the degree of postoperative pain; a threefold higher frequency of PONV has been reported in ambulatory surgery patients with postoperative pain.¹⁴²

Anesthetic Agents With a Low Incidence of Postoperative Nausea and Vomiting

21. How could J.E.'s anesthetic regimen have been modified to reduce the likelihood of PONV?

Several changes could be made in the anesthetic regimen to reduce the likelihood of PONV. When propofol is used for both induction and maintenance of anesthesia, it reduces the risk of PONV similar to the administration of a single antiemetic.¹³⁹ Because perioperative administration of opioids is associated with PONV, the use of NSAIDs (oral agents preoperatively and postoperatively, parenteral ketorolac intraoperatively and postoperatively), when appropriate, can reduce the need for postoperative opioids. In addition, surgical wound infiltration with a long-acting local anesthetic, such as bupivacaine, should also be used, as needed, to reduce postoperative incisional pain.

Analgesic Agents and Postoperative Pain Management

Acute Pain

Surgery causes injury to the body, resulting in acute pain. Specifically, the tissue trauma from surgery directly stimulate nociceptors (receptors in the periphery that detect damaging or unpleasant stimuli, inflammation, pressure, and/or temperature). In addition, tissue injury causes the release of inflammatory mediators (e.g., prostaglandins, substance P) that sensitize and activate nociceptors. Sensitized nociceptors amplify the pain impulse by generating nerve impulses more readily and more often; this is called “peripheral sensitization.” The pain impulse then travels from the periphery to the dorsal horn of the spinal cord. From here, the pain impulse ascends to higher centers in the brain, which results in the patient “feeling” the pain. Because both cortical and limbic systems are involved and social and environmental influences are present, the same surgery can result in significant individual differences in pain perception. Persistent bombardment of the dorsal horn with pain impulses from the periphery results in central sensitization (“wind-up”), where there is increased firing of dorsal horn neurons. Clinically, when these two processes occur, the patient will experience a lower pain threshold, both at the site of injury and in the surrounding tissue. When this occurs, pain may be prolonged beyond the usual expected duration following surgery. If central sensitization is prolonged, permanent changes in the CNS can occur. Clinically, this can result in postoperative pain that is hard to manage.^143,144

The degree of pain usually depends on the magnitude of the surgery¹⁴⁵ and the patient's level of fear and anxiety. Patients vary in their response to pain (and interventions) and in their personal preferences toward pain management. Acute pain usually resolves when the injury heals (hours to days). Unrelieved acute postoperative pain has detrimental physiological and psychological effects, including impaired pulmonary function (leading to pulmonary complications); thromboembolism; tachycardia; hypertension and increased cardiac work; impairment of the immune system; nausea, vomiting, and ileus; chronic pain; and anxiety, fatigue, and fear.¹⁴⁶

Adequate pain assessment and management are essential components of perioperative care. Education of patients and families about their roles, as well as the limitations and side effects of pain treatments, is critical to managing postoperative pain. Pain management must be planned for and integrated into the perioperative care of patients. Proactive planning includes obtaining a pain history based on the patient's own experiences with pain; determining the patient's pain goal; and anticipating preoperative, intraoperative, and postoperative pain therapies. The intensity and quality of pain, as well as the patient's response to treatment and the degree to which pain interferes with normal activities, should be monitored. Ideally, pain should be prevented by treating it adequately because once established, severe pain can be difficult to control.

Management Options

Effective postoperative pain management should provide subjective pain relief while minimizing analgesic-related adverse effects, allow early return to normal daily activities, and minimize the detrimental effects from unrelieved pain. The following techniques can be used to manage postoperative pain: (a) systemic administration of opioids, NSAIDs, and acetaminophen; (b) on-demand administration of IV opioids, also known as patient-controlled analgesia (PCA); (c) epidural analgesia (continuous and on-demand, usually with an opioid/local anesthetic mixture); (d) local nerve blockade such as local infiltration or peripheral nerve block; and (e) application of heat or cold, guided imagery, music, relaxation, or other nonpharmacologic intervention. Local anesthetics, opioids, acetaminophen, and NSAIDs can be used alone or in combination to create the optimal analgesic regimen for each patient based on factors such as efficacy of the agent to reduce pain to an acceptable level, type of surgery, underlying disease, adverse effects, and cost of therapy. For patients experiencing mild to moderate postoperative pain, local anesthetic wound infiltration or peripheral nerve blockade, or administration of a nonopioid analgesic such as an NSAID or acetaminophen are appropriate approaches to analgesia. For moderate postoperative pain, a less potent oral opioid, such as hydrocodone or codeine, is added. For moderate to severe pain following more invasive surgery, an IV opioid (e.g., morphine, hydromorphone), an epidural containing a local anesthetic and opioid, or a peripheral nerve block with local anesthetic is necessary. (For more information about general pain management, see Chapter 8.) Analgesia for acute pain in the perioperative setting is best achieved by using a multimodal (balanced) approach with a combination of two or more analgesic agents that have different mechanisms of action or that are administered by different techniques.¹⁴⁶

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Cardioplegia Solution

Cardioplegia Solution

Use in Cardiac Surgery

Hypothermic, hyperkalemic cardioplegia solution was first used in open heart surgery in the 1970s and enjoys widespread clinical use today. Cardioplegia solution is infused into the coronary vasculature to produce an elective diastolic cardiac arrest. Inducing cardiac arrest, or cardioplegia, helps protect the myocardium while providing the surgeon with a still, bloodless operative field and a flaccid heart on which to work. Cardioplegia solution is administered via the cardiopulmonary bypass pump (a heart-lung machine) through specialized circuits.

During open heart surgery, the heart is excluded from normal circulation by diverting venous blood away from the right atrium via gravity drainage and by clamping the aorta. Systemic circulation of blood is maintained through the use of the cardiopulmonary bypass pump; a cannula is placed in the aorta distal to the clamp and carries oxygenated blood from the pump to the patient. The blood circulates through the body and is returned to the cardiopulmonary bypass pump through cannulas inserted into the superior and inferior venae cava.

Delivery Methods

Cardioplegia solution is delivered to the coronary circulation by three approaches: antegrade, retrograde, or combination antegrade/retrograde. With antegrade administration, the solution is administered via a cannula placed in the aortic root, whereas with retrograde administration, the cannula is placed in the coronary sinus.⁸⁹ The commonly used combination approach eliminates problems such as the nonhomogeneous distribution of cardioplegia solution, which can occur with the antegrade approach, while still ensuring a rapid arrest (arrest produced by retrograde administration is not as fast as antegrade).^90,91 This approach has significantly reduced patient morbidity when compared with antegrade administration, especially in high-risk patients requiring reoperation.⁹⁰

Phases of Cardioplegia

Cardioplegia can be divided into three phases: induction of arrest, maintenance of arrest, and reperfusion (immediately before aortic unclamping). Cardioplegia solution is used routinely during the induction and maintenance phases, and reperfusion solution is used at the end of surgery before aortic unclamping. The solutions used in each phase may differ in composition and characteristics.

Goal of Treatment

Cardioplegia solution is used to prevent myocardial ischemic damage that can occur during the induction and maintenance of arrest, whereas reperfusion solution is used to help prevent and minimize the destructive phenomena that can occur during reperfusion. Myocardial ischemia can result in a number of detrimental changes to the heart, including rapid cellular conversion from aerobic to anaerobic metabolism, high-energy phosphate (e.g., adenosine triphosphate [ATP]) depletion, intracellular acidosis, calcium influx, and myocardial cell membrane disruption. Destructive changes that can occur during reperfusion include intracellular calcium accumulation, explosive cell swelling, and inability to use delivered oxygen.⁹² Chemical components are added to cardioplegia solution to counteract the specific cellular effects of ischemia and the cellular events that can occur during reperfusion.

Table 9-13 Advantages and Disadvantages of Cardioplegia Solution Vehicles

Vehicle Advantages Disadvantages Blood Oxygen-carrying capacity Possible sludging at low temperatures   Active resuscitation Possible unfavorable shift in oxyhemoglobin association curve   Reduction in systemic hemodilution Potential for poor distribution of solution beyond coronary stenoses   Minimize reperfusion damage Possible red blood cell crenation   Provision of inherent buffering, oncotic, and rheologic effects Impaired visualization   Provision of physiological calcium concentration     Presence of endogenous oxygen-free radical scavengers   Crystalloid History of effectiveness Minimal oxygen-carrying capacity   Ease of solution preparation Possible damage of coronary endothelium   Low cost Minimal potential for capillary obstruction Reduced efficacy (compared with blood) in preserving left ventricular function postoperatively     Systemic hemodilution     Possible role in production of late myocardial fibrosis Adapted from references 89, 90, and 93.

Cardioplegia Solution Vehicles

The chemical composition of a cardioplegia solution depends on the vehicle used: blood or crystalloid. Each has advantages and disadvantages, as can be seen in Table 9-13.^89,90,93 Blood, because of its many advantages, is the vehicle most commonly used. Blood cardioplegia provides oxygen while the heart is arrested, proteins in blood maintain osmotic pressures closer to normal and are capable of serving as buffers, and endogenous oxygen-free radical scavengers are beneficial during reperfusion.⁹³ The disadvantages listed for blood have not been shown to occur during clinical use of blood-based cardioplegia solution. The patient's own hemodiluted blood from the extracorporeal circuit is used. Blood-based cardioplegia solution delivery systems include commercially available microprocessor-controlled pumps that are capable of directly injecting an additive into the blood as well as more conventional systems that deliver a fixed ratio of blood with a premixed crystalloid cardioplegia solution. Ratios of blood to crystalloid composition range from 1:1 to 16:1. The concentration of additives in the crystalloid solution must be tailored to the specific delivery ratio used to prevent accidental overdosage or underdosage. A commonly used ratio in clinical practice today is 4:1; in other words, the blood-based cardioplegia solution being delivered to the patient contains four parts blood to one part crystalloid solution. Therefore, the concentration of additives contained in the crystalloid solution is five times greater than that actually delivered to the patient due to the dilution of this solution with blood before it reaches the patient. Furthermore, with blood-based cardioplegia solution, there is a reduced need to place additives in the crystalloid component of the solution. For example, calcium and magnesium need not be added to the crystalloid component because sufficient quantities are contained in blood.

Common Characteristics

Most cardioplegia solutions have certain basic characteristics in common. Crystalloid cardioplegia solutions are made hyperosmolar to help minimize myocardial edema associated with cardiac arrest and are usually made slightly basic to compensate for the metabolic acidosis that accompanies myocardial ischemia. Cardioplegia solutions are traditionally chilled to a temperature of 4°C to 8°C before being infused into the coronary circulation. Hypothermia decelerates the metabolic activity of the heart, reduces myocardial oxygen demand and the detrimental effects seen with myocardial ischemia, and helps maintain cardiac arrest.^94,95 However, hypothermia can also produce deleterious effects on the heart, including impaired mitochondrial energy generation and substrate utilization, membrane destabilization, and the need for a longer period of reperfusion to rewarm the heart, which can increase the chances of reperfusion injury. In an effort to minimize the adverse consequences of hypothermia, the use of normothermic cardioplegia solution for induction of arrest (with cardioplegia maintained with a hypothermic solution) and the administration of a normothermic reperfusion solution before aortic cross-clamp removal was demonstrated to improve myocardial metabolic and functional recovery in energy-depleted hearts.⁹³ The benefits seen with this technique prompted investigators to study the use of intermittent, normothermic (37°C) cardioplegia. Positive results were reported with this technique and included a decreased incidence of perioperative myocardial infarction (MI) and need for intra-aortic balloon pump (IABP) support, as well as a lower incidence of postoperative low cardiac output syndrome.^96,97 However, studies examining the use of normothermic cardioplegia solution have not consistently demonstrated a decrease in mortality or perioperative MI when compared with hypothermic cardioplegia solution. With normothermic cardioplegia, a major concern is that not as much protection from ischemia is provided during the time that cardioplegia solution is not being infused as that provided with the use of hypothermic solution. Furthermore, when compared with hypothermic cardioplegia solution, warm cardioplegia is associated with a greater use of crystalloid and α-agonists to maintain perfusion pressure, higher total volumes of cardioplegia, increased use of high-potassium cardioplegia to stop periodic episodes of electrical activity, a higher incidence of systemic hyperkalemia, and lower systemic vascular resistance.⁹⁸ In an attempt to reduce problems seen with normothermic cardioplegia, the use of tepid (29°C) cardioplegia solution has been advocated. When compared with hypothermic techniques, tepid cardioplegia resulted in greater left and right ventricular stroke work indices (slightly less than normothermic cardioplegia) and a much faster recovery of myocardial function.^99,100 Currently, a combination normothermic/hypothermic technique is still used more frequently in practice. Additional work is needed in this area.

Additives

Table 9-14 presents additives commonly used in cardioplegia and/or reperfusion solutions, the reason for their addition, and frequently used concentrations.^89,90 In addition to these additives, several other classes of agents continue to be examined for their usefulness in cardioplegia and/or reperfusion solutions.

Oxygen-free Radical Scavengers

Oxygen-free radicals (e.g., superoxide anion, hydrogen peroxide, free hydroxyl radical) are released during the sudden reintroduction of oxygen to ischemic tissue during reperfusion. They have been implicated in myocyte death, reperfusion-induced arrhythmias, and prolonged left ventricular dysfunction after reperfusion.⁹² The addition to reperfusion solution of drugs that inhibit oxygen-free radical production or degrade free radicals (e.g., mannitol, deferoxamine, allopurinol) has been demonstrated to reduce post-reperfusion myocardial injury and other free radical-induced surgical complications.^101,102,103 An advantage of using blood-based cardioplegia solution is that blood contains endogenous oxygen-free radical scavengers (e.g., catalase, superoxide dismutase, glutathione).¹⁰⁴

Adenosine

Adenosine is an endogenous nucleoside that is released from the ischemic myocardium during the catabolism of ATP. It protects the heart from ischemic and reperfusion injury and may have a role in ischemic preconditioning. Adenosine produces the majority of its effects through interaction at the adenosine A1, A2, and A3 receptors. Stimulation of A1 receptors causes activation of the ATP-sensitive potassium channel (K-ATP), ultimately resulting in positive chronotropic and dromotropic effects, antiadrenergic effects, stimulation of glycogenolysis, and stimulation of neutrophil adherence. Stimulation of A2 receptors results in vasodilation, renin release, inhibition of neutrophil adherence to endothelium, and inhibition of superoxide generation. The physiological effects of stimulation of A3 receptors include inhibition of neutrophil adherence to endothelium.¹⁰⁵ The cardioprotective effects during preconditioning are believed to be the result of K-ATP channel activation. Preliminary results of a phase II trial found that adenosine may improve postoperative hemodynamic function and possibly reduce morbidity and mortality when patients receive IV adenosine immediately before and after aortic cross-clamping in addition to cold blood cardioplegia containing 2 mM adenosine.¹⁰⁶ However, further multicenter studies are needed to identify patients who will benefit the most from adenosine and whether adenosine will definitively reduce the incidence of MI or death following open heart surgery.

L-Arginine

Ischemia results in decreased formation of nitric oxide; nitric oxide helps prevent neutrophils from adhering to the vascular endothelial cells. Neutrophil adhesion to the coronary endothelium is a prerequisite for neutrophil activation and accumulation in the myocardium. Activated neutrophils may be a major source of oxygen-free radical production. They enhance degranulation and the release of proteases, which cause cellular damage, and they adhere to microvascular endothelium or embolize in the microcirculation. Nitric oxide–dependent vasodilation and inhibition of neutrophil activity are believed to play important roles in preventing reperfusion damage after ischemia.

Table 9-14 Commonly Used Cardioplegia Solution Additives

Additive Frequently Used Concentrationa Function Amino acid substrates (glutamate/aspartateb) 11–12 mL/Lc Improves myocardial metabolism; improves metabolic and functional recovery in energy-depleted hearts Calcium At least trace amounts (0.1 mEq/L) Maintains integrity of myocardial cell membrane; prevents “calcium paradox”d Chloride 90–110 mEq/L Establishes a solution similar in composition to extracellular fluid CPD solution 12 mL/Le 45 mL/Lc Chelates calcium in blood-based cardioplegia solution to produce safe levels of hypocalcemia for rapid diastolic arrest; limits postischemic calcium accumulation and improves postischemic performance Glucose 5–10 g/L safely used Helps achieve desired osmolarity of solution; serves as a metabolic substrate for the heart Magnesium 32 mEq/L Reduces magnesium loss during ischemia; reduces calcium influx and potassium efflux during ischemia; has a weak arresting action on heart Potassium 15–30 mEq/Lf Induces rapid diastolic arrest Sodium 120–140 mEq/L Necessary for protective action of potassium; establishes a solution similar in composition to extracellular fluid Sodium bicarbonate or THAM Variable; added until desired pH is obtained Provides buffering capacity; helps maintain physiologically normal pH range; counters acidosis produced by ischemia aConcentration delivered to patient; concentration dependent on other cardioplegia solution additives (concentration of any one additive may be changed by inclusion of other additives). bNot commercially available in parenteral formulation; each milliliter of solution contains 178.4 mg monosodium L-glutamate and 163.4 mg monosodium L-aspartate (for preparation directions, see reference 89). cWarm, blood-based induction and reperfusion solutions. dCalcium paradox is a condition that results in rapid consumption of high-energy phosphates, extensive ultrastructural damage of myocardial cells, and myocardial contracture; it results from an influx of calcium into the myocardial cells, resulting from the introduction of a calcium-containing perfusate (i.e., blood) into the system during reperfusion after the use of a cardioplegia solution completely lacking in calcium. eCold, blood-based induction and maintenance solutions. fLower concentrations (5-10 mEq/L) used during maintenance phase. CPD, citrate-phosphate-dextrose; THAM, trishydroxymethylaminomethane. Adapted from references 89 and 90.

L-arginine is a nitric oxide donor and may have a role as a supplement to cardioplegia and/or reperfusion solutions. Animal studies have demonstrated benefits (reduction in oxygen-free radical formation, restoration of endothelial function) from the addition of L-arginine to cardioplegia solutions.^107,108,109 Limited trials in patients undergoing coronary artery bypass grafting have demonstrated that the addition of L-arginine (7.5 g/500 mL) to blood cardioplegia reduced the release of cardiac troponin T, a marker of myocardial ischemia.¹¹⁰

Potassium

16. W.D., a 64-year-old man, ASA-III, is scheduled to undergo a coronary artery bypass graft. W.D.'s serum potassium concentration is 4 mEq/L. A blood-based cardioplegia solution is ordered for the patient with the concentration of potassium in the crystalloid component to be 76 mEq/1,000 mL. Cold induction (e.g., chilled cardioplegia solution) using a delivery system of four parts blood to one part cardioplegia solution will be used. On administration of the solution to W.D., cardiac arrest was not achieved. A STAT chemical analysis of the crystalloid solution revealed that it contained no potassium. Why is this consistent with the findings in W.D.?

Failure to see immediate arrest within 1 to 2 minutes after the administration of cardioplegia solution can be due to several factors, including incomplete aortic clamping, aortic insufficiency, and failure to have a potassium concentration sufficient to produce arrest. Because W.D.'s cardioplegia solution contained no potassium, a direct cause-and-effect relationship can be made to the inability to achieve an arrest.

The major role of potassium in cardioplegia solution is to induce a rapid diastolic arrest by blocking the inward sodium current and initial phases of cellular depolarization. This results in cessation of electromechanical activity and helps preserve ATP and creatine phosphate stores for postischemic work. A delivered potassium concentration in the range of 15 to 20 mEq/L is used most commonly. This concentration has consistently produced asystole while minimizing adverse effects (e.g., tissue damage, systemic hyperkalemia). Potassium concentrations >40 mEq/L alter myocardial cell membranes, allow extracellular calcium to enter the cell, and raise energy demands.¹¹¹ In laboratory studies, high concentrations of potassium (>100 mEq/L) increase myocardial contracture and wall tension, a condition referred to as stone heart syndrome.¹¹² Varying concentrations of potassium are used in the cardioplegia solution, depending on the phase of cardioplegia. As previously discussed, a high concentration of potassium is required to induce arrest, whereas lower concentrations (e.g., 5-10 mEq/L) are sufficient to maintain arrest.¹¹³ On first glance, the concentration of potassium ordered in W.D.'s blood-based cardioplegia solution appears excessive. However, the concentration delivered to the coronary circulation is slightly <20 mEq/L if one considers that the potassium contribution from the blood component of this blood-based cardioplegia solution is approximately 4 mEq/L and that from the crystalloid component is approximately 15 mEq/L (76 mEq/L / 5). This highlights the importance of knowing the delivery ratio being used for the administration of blood-based cardioplegia solution.

Amino Acids: Normothermic, Blood-Based Cardioplegia Solution

17. T.E., a 55-year-old man, ASA-IV, is admitted to the hospital with an MI. He is currently in the coronary care unit and is scheduled for myocardial revascularization surgery. He has poor left ventricular function (cardiac output, 2.2 L/minute [normal, 4–6 L/minute]; pulmonary capillary wedge pressure, 25 mmHg [normal, 5–12 mmHg]; left ventricular ejection fraction, 25% [normal, >60%]), and is on an IABP for circulatory support. In addition to being on the IABP, he is receiving dopamine and milrinone. A diagnosis of cardiogenic shock is made. What type of cardioplegia solution should T.E. receive during his revascularization surgery?

Normothermic (37°C), blood-based cardioplegia and reperfusion solutions containing the amino acids glutamate and aspartate have been advocated for the induction and reperfusion phases of cardioplegia in patients with ischemic hearts (e.g., extending MI, cardiogenic shock, hemodynamic instability) or those with advanced left or right ventricular hypertrophy or dysfunction.^114,115,116 Glutamate and aspartate, Krebs' cycle precursors, are added to cardioplegia solution to counteract the depletion of Krebs' cycle intermediates during myocardial ischemia and to enhance energy production during reperfusion.^114,116,117 These agents enhance oxidative metabolism optimally at normothermia (37°C).¹¹⁷

With this technique, cardioplegia induction is accomplished with an infusion of the normothermic, blood-based cardioplegia solution over 5 minutes. Normothermia optimizes the rate of cellular repair, whereas glutamate and aspartate improve oxygen utilization capacity.¹⁰³ The normothermic solution is immediately followed by a 5-minute infusion of hypothermic, blood-based cardioplegia solution. Cardioplegia is maintained with hypothermic, blood-based solution. Normothermic reperfusion solution is administered for 3 to 5 minutes immediately before aortic unclamping (reperfusion). The administration of normothermic solution at the conclusion of surgery is referred to by some as a hot shot. It is believed to result in early resumption of temperature-dependent mitochondrial enzymatic function and to allow energy supplies to be channeled into cellular recovery rather than electromechanical work. This results in improved hemodynamic and myocardial metabolic recovery.^117,118

T.E., with his poor myocardial function, is a suitable candidate to receive amino acid–enriched, normothermic, blood-based cardioplegia solution and reperfusion solution during the induction and reperfusion phases of cardioplegia, respectively.

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