A Practical Approach to Cardiac Anesthesia (Practical Approach Series) 5th Ed.

27 Pain Management for Cardiothoracic Procedures

Mark Stafford-Smith and Thomas M. McLoughlin, Jr.


 1. Chronic pain due to intercostal nerve injury develops in approximately 50% of postthoracotomy patients, and in 5% this pain becomes severe and disabling.

 2. Thoracic epidural analgesia for cardiac surgery is associated with reduced supraventricular arrhythmias and postoperative pulmonary complications relative to standard approaches.

 3. Highly lipophilic drugs, such as fentanyl, are best used with catheters placed near the involved dermatomes. Hydrophilic drugs, such as morphine, are most useful for remote catheters such as those positioned in the lumbar region.

 4. Epidural opioids should generally not be administered unless postoperative observation and monitoring for delayed respiratory depression are planned.

 5. Patients with severe lung disease have the most to gain in terms of improved outcome from optimal postoperative analgesia such as continuous thoracic epidural.

 6. The risk of nephrotoxicity appears to be low (1:1,000 to 1:10,000) with perioperative ketorolac administration.

 7. Respiratory depression requiring naloxone administration is reported to occur in 0.2% to 1% of patients receiving epidural narcotics.

 8. Pending additional contributions to our understanding of the risk of peridural bleeding, the trend in expert opinion has recently shifted to argue for caution, particularly regarding thoracic epidural catheter placement prior to “full” heparinization for cardiac surgery.


I. Introduction

   A. Incidence and severity of pain after cardiothoracic procedures. Pain is an unpleasant sensation occurring in varying degrees of severity as a consequence of injury or disease. Chest surgery, via sternotomy and especially via thoracotomy, is among the most debilitating for patients due to pain and consequent respiratory dysfunction. Important sources of postoperative discomfort after cardiothoracic surgery, in addition to incisional pain, include indwelling thoracostomy tubes, rib or sternal fractures, and costovertebral joint pain due to sternal retraction. Chronic pain due to intercostal nerve injury develops in approximately 50% of postthoracotomy patients, and in 5% this pain becomes severe and disabling. Despite the early belief that minimally invasive thoracic and cardiac surgical procedures involving smaller incisions would reduce the incidence and severity of postoperative pain compared to traditional cardiac surgery, clinical experience has not borne out this assumption for most patients. No single thoracotomy technique has been shown to reduce the incidence of chronic postthoracotomy pain, and patients should be warned in advance of this potential postoperative complication.

   B. Transmission pathways for nociception. An understanding of the anatomy and physiology of pain pathways underpins the logical choice of analgesic strategies during and after cardiothoracic surgery. Multimodal approaches take advantage of numerous therapeutic targets in the signaling chain to optimize pain control while minimizing side effects [1].

   In the thoracic region, pain signals are relayed through myelinated Aδ and unmyelinated C fibers in peripheral intercostal nerves. The ventral, posterior, and visceral branches of each intercostal nerve innervate the anterior chest wall, posterior chest wall, and visceral aspects of the chest, respectively. These branches join together just before entering the paravertebral space and then pass through the intervertebral foramina in the spinal canal. Sensory intercostal nerve fibers form a dorsal root that fuses with the spinal cord dorsal horn to enter the central nervous system (CNS). Somatic pain is mediated predominantly through myelinated Aδ fibers in the ventral and posterior branches. Sympathetic (visceral) pain is mediated by unmyelinated C fibers in all three branches. Sympathetic afferent pain signals are directed from intercostal nerve branches through the sympathetic trunk (a paravertebral structure found just beneath the parietal pleura in the thorax) and then pass back into the peripheral nerves to enter the CNS from T-1 to L-2. In addition, the vagus nerve provides parasympathetic visceral innervation of the thorax. This cranial nerve enters the CNS through the medulla oblongata and, therefore, is not normally affected by epidural or intrathecal (IT) methods of pain control.

   The spinal cord and spinal canal are considerably different in length, and consequently spinal cord dermatomal segments do not typically lie at the level of their respective vertebrae. Thus, knowledge of spinal anatomy is essential if regional analgesia techniques are to be successful. This is particularly true with the use of lipid-soluble epidural opioids because the targeted dorsal horn often is significantly cephalad relative to the associated intervertebral foramen and nerve.

   Most spinal pain signals are transmitted to the brain after crossing from the dorsal horn to contralateral spinal cord structures (e.g., spinothalamic tract). Distribution of nociceptive messages occurs to numerous locations in the brain resulting in cognitive, affective, and autonomic responses to noxious stimuli.

   Endogenous modification of pain signals begins at the site of tissue trauma and includes hyperalgesia related to inflammation and other CNS-mediated phenomena such as “windup.” The substantia gelatinosa of the dorsal horn is an important location for pain signal modulation, including effects that are mediated through opioid, adrenergic, and N-methyl-D-aspartate (NMDA) receptor systems.

   C. Analgesia considerations: The procedure, patient, and process. The degree and location of surgical trauma, particularly in relation to the site of skin incision and route of bony access to the chest, are particularly important in anticipating analgesic requirements after cardiothoracic surgery. Notably, minimally invasive procedures that reduce total surgical tissue disruption but relocate it to more pain-sensitive regions may not translate into reduced postoperative pain (e.g., minithoracotomy vs. sternotomy). Analgesic strategies are best individualized, particularly for high-risk patients in whom outcome benefits may be the greatest. This includes not only appropriate postoperative analgesia delivery but also preoperative education regarding pain reporting, procedures, and devices to provide analgesia, and expectations for postoperative transition to oral medications and home administration.

   D. Adverse consequences of pain. In addition to unpleasant emotional aspects of pain, nociceptive signals have several other effects that can be harmful and delay patient recovery. These include activation of neuroendocrine reflexes constituting the surgical stress response (including inflammation and elevated circulating catecholamines), a catabolic state associated with high levels of several other humoral substances (e.g., cortisol, vasopressin, renin, angiotensin), decreased vagal tone, and increased oxygen consumption. Spinal reflex responses to pain include localized muscle spasm and activation of the sympathetic nervous system.

   Pathophysiologic consequences of the neuroendocrine local and systemic responses to pain include respiratory complications related to diaphragmatic dysfunction, myocardial ischemia, ileus, urinary retention and oliguria, thromboembolism, and immune impairment [2].


   E. Outcome benefits of good analgesia for cardiothoracic procedures. A primary benefit of effective pain control is patient satisfaction. Studies have documented additional advantages of optimizing analgesia, especially in recovery from thoracotomy. Belief that the pain of median sternotomy is less severe and inconsequential to outcome leads many institutions to employ conventional analgesia protocols involving fixed dosing of analgesics on a timed schedule. However, after coronary bypass grafting, attention to profound analgesia in the early postoperative period may decrease the incidence and severity of myocardial ischemia. A meta-analysis of 28 randomized studies suggests that thoracic epidural analgesia for cardiac surgery is associated with reduced supraventricular arrhythmias and postoperative pulmonary complications relative to standard approaches [3].

   Evidence supporting reductions in perioperative complications related to pain relief are reported for many different analgesia techniques and may be related to their effectiveness in blocking the surgical stress response and nociceptive spinal reflexes. In this regard, neuraxial and regional analgesia are most often reported as being effective. Nonetheless, beyond reduced pain, any outcome benefits related to the incidence of major morbidities and mortality of specific analgesia techniques remain difficult to prove, possibly due to the insufficient numbers of patients studied and the low frequency of these events, as is well summarized in a review by Liu et al. [4]. In general, reported benefits of good analgesia rely on reporting of surrogate markers that correlate with major adverse outcomes (e.g., arterial oxygen saturation) that imply attenuation of the adverse consequences of pain outlined in Section I.D. For example, in the setting of thoracic surgery, thoracic epidural analgesia provides superior pain relief compared to systemic opioids and decreases the incidence of atelectasis, pulmonary infections, hypoxemia, and other pulmonary complications [5]. In addition, effective analgesia established before surgery in some circumstances may provide pre-emptive protection against the development of chronic pain syndromes. Aggressive pain control in the early postoperative period was associated with a greater than 50% reduction in the number of patients continuing to experience chronic pain 1 year after thoracotomy in one study [6]. Unfortunately, in cardiac surgery, reports of neuraxial techniques generally involve small numbers and fail to demonstrate clinical outcome benefit, although benefits in hospital length of stay and cost avoidance have been commonly shown [7]. Outcome benefit following cardiac surgery with central neuraxial analgesia was not demonstrated in a meta-analysis published in 2004 nor in a randomized trial published in 2011 [8,9].

II. Pain management pharmacology

   A. Opioid analgesics

     1. Mechanisms. Opioid analgesics are a broad group of compounds that include naturally occurring extracts of opium (e.g., morphine, codeine), synthetic substances (e.g., fentanyl, hydromorphone), and endogenous peptides (e.g., endorphins, enkephalins). The analgesic effects of these drugs are all linked to their interaction with opioid receptors; however, individual agents may function as agonists, antagonists, or partial agonists at different receptor subtype populations. Opioid receptors are widely distributed throughout the body, but they are particularly concentrated within the substantia gelatinosa of the dorsal horn of the spinal cord, as well as regions of the brain including the rostral ventral medulla, locus ceruleus, and midbrain periaqueductal gray area. Stimulation of opioid receptors inhibits the enzyme adenyl cyclase, closes voltage-dependent calcium channels, and opens calcium-dependent inwardly rectifying potassium channels, resulting in inhibitory effects characterized by neuronal hyperpolarization and decreased excitability. Opioid receptor subtypes have been sequenced and cloned, and they belong to the growing list of G-protein-coupled receptors. The effects of agonist binding at different opioid receptor subtypes are summarized in Table 27.1.

Table 27.1 Opioid receptors


     2. Perioperative use. Opioids are commonly administered throughout the perioperative period for cardiothoracic procedures. Preoperatively, they can be given orally, intramuscularly (IM), or intravenously (IV) alone or as part of a sedative cocktail to provide anxiolysis and analgesia for transport and placement of intravascular catheters. Intraoperatively, they are given IV most commonly as part of a balanced anesthetic technique that includes potent inhaled anesthetics, benzodiazepines, and other agents. Finally, they can be injected directly into the thecal sac or included as a component of epidural infusions to provide intraoperative and postoperative analgesia. Opioids administered epidurally have varying spread and analgesic potency based in part on their water solubility and are best matched with analgesic requirements with knowledge of the position of the epidural catheter relative to the dermatomes affected by pain and the relative lipophilicity of the drug. Highly lipophilic drugs, such as fentanyl, are best used with catheters placed near the involved dermatomes. Hydrophilic drugs, such as morphine, are most useful for remote catheters such as those positioned in the lumbar region. Drugs with intermediate lipophilicity, such as hydromorphone, are considered ideal by most and can be used for more balanced spread.

     3. Side effects and cautions

        a. Respiratory depression (increased risk with higher dosing, coadministration of other sedatives, opioid-naive patients, advanced age, central neuraxial administration of hydrophilic opioid agents)

        b. Sedation

        c. Pruritus

        d. Nausea

        e. Urinary retention, especially common in the elderly and in males receiving spinal opioids

        f. Inhibition of intestinal peristalsis/constipation

        g. CNS excitation/hypertonia, much more notable with rapid IV administration of lipophilic agents

        h. Miosis

        i. Biliary spasm

        All of the above effects can be reversed with administration of opioid antagonist drugs (e.g., naloxone). Opioid rotation, or changing the narcotic drug that a patient is receiving, may also be useful in reducing the incidence or severity of complicating side effects or also in enhancing the patient’s experience of analgesia [10].

   B. Nonsteroidal anti-inflammatory drugs

     1. Mechanisms. Nonsteroidal anti-inflammatory drugs (NSAIDs) act principally through both central and peripheral inhibition of cyclo-oxygenase, resulting in decreased synthesis of prostaglandins from arachadonic acid, including prostacyclin and thromboxane. Prostaglandins are involved in the physiology of numerous signaling pathways, including those influencing renal perfusion, bronchial smooth muscle tone, hemostasis, the gastric mucosal secretions, and the inflammatory response. Prostaglandin E2 is the eicosanoid produced in greatest quantity at sites of trauma and inflammation and is an important mediator of pain. The full therapeutic effects of NSAIDs are complex and likely involve mechanisms that are independent of prostaglandin effects. For example, prostaglandin synthesis is effectively inhibited with low doses of most NSAIDs; however, much higher doses are required to produce anti-inflammatory effects.

     2. Perioperative use. NSAIDs are useful for postoperative analgesia. They are most commonly administered in cardiothoracic surgical patients as a complement to neuraxial techniques. Their principal advantage is the absence of respiratory depression and other opioid side effects. Many NSAIDs are available for oral or rectal administration. Ketorolac is a non-selective NSAID intended for short-term use (5 days or less) with preparations available for intravenous or intramuscular injection, in addition to tablets for ingestion.

     3. Side effects and cautions

        a. Decreased renal blood flow/parenchymal ischemia

        b. Gastrointestinal mucosal irritation

        c. Impaired primary hemostasis

     4. COX-2 inhibitors

The effects of cyclo-oxygenase are mediated by two distinct isoenzymes termed COX-1 and COX-2. COX-1 is the constitutive form responsible for production of prostaglandins involved in homeostatic processes of the kidney, gut, endothelium, and platelets. COX-2 is predominantly an inducible isoform responsible for production of prostaglandins during inflammation. Highly selective COX-2 inhibitors have potent analgesic properties and, until recently, were used frequently to treat perioperative pain. Unfortunately, combined data from several large randomized double-blind trials [11] revealed an increased incidence of cardiovascular complications including myocardial infarction with agents in this drug class. Celecoxib is the only remaining COX-2 inhibitor widely available for prescription in the US. The difference between celecoxib and the other agents may be due to its relatively modest COX-2 versus COX-1 subtype selectivity compared to the other agents (30 : 1 vs. >300 : 1). However, celecoxib use remains largely limited to treatment of severe arthritis, rheumatoid arthritis, and ankylosis spondylitis in circumstances where treatment of these conditions with several other NSAIDs has failed. Prothrombotic effects from COX-2 inhibition are likely due to reduced prostacyclin generation. In addition, COX-2 inhibitors lack the antiplatelet effects of aspirin and even favor vasoconstrictive effects. Thus, use of these agents for perioperative pain relief is not recommended.

   C. Acetaminophen (paracetamol)

     1. Mechanism

Acetaminophen is a synthetic, non-opiate, analgesic drug that is distinct from most other NSAIDs in that it is a weak inhibitor of the synthesis of prostaglandins and of COX-1 and COX-2. Its mechanisms appear to be primarily central, resulting in analgesia and antipyresis, with only minimal anti-inflammation. COX-3, a splice variant of COX-1, has been suggested to be the site of action. Other proposed actions include activation of descending serotonergic pathways and/or inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including NMDA and substance P. Although the exact site and mechanism of analgesic action is not clearly defined, acetaminophen appears to produce analgesia by elevation of the pain threshold.

     2. Perioperative use and cautions

Until recently, acetaminophen was only available for oral and rectal administration and thus infrequently used in the immediate perioperative period. In 2010, the FDA approved an intravenous form of the drug for relieving pain or fever in surgical patients, approved for use in adults and children aged 2 and older. It has been shown useful in the treatment of moderate to severe post-surgical pain, demonstrating an opioid-sparing effect with good patient acceptance and few adverse effects, especially in orthopedic surgical populations [12]. A modest opioid-sparing effect, with no reduction in the incidence of nausea and vomiting, was shown when intravenous acetaminophen was compared to oral acetaminophen in a postoperative population of coronary artery bypass surgical patients [13].

          The primary risk of acetominaphen is hepatotoxicity secondary to overdose. Acetaminophen toxicity is the leading cause of acute liver failure in the United States. A typical intravenous adult dosing schedule involves administration of 650 to 1,000 mg every 6 hrs, with infusion of the drug timed to occur over at least 15 min.

   D. Local anesthetics

     1. Mechanisms. Local anesthetics interrupt neural conduction thus disrupting transmission of pain and other nerve impulses through blockade of neuronal voltage-gated sodium channels. This blockade does not change the resting potential of the nerve. However, altered sodium ion channel permeability slows depolarization such that, in the presence of a sufficient concentration of local anesthetic, threshold for propagation of an action potential cannot be reached.

     2. Perioperative use. Local anesthetics are used throughout the perioperative period for topical, infiltration, peripheral nerve, or central neuraxial anesthesia. Their advantage lies in the capacity to provide profound analgesia without the undesired side effects seen with opioids or NSAIDs. Effective regional anesthesia is the best technique to most completely attenuate the neurohumoral stress response to pain. Thoracic epidural analgesia is particularly useful in treating pain, both somatic and visceral, for patients with occlusive coronary artery disease.

     3. Side effects and cautions

        a. Not surprisingly, side effects from sodium channel blockade due to local anesthetic toxicity resemble those observed with severe hyponatremia. Excessive local anesthetic blood concentrations, reached through absorption or inadvertent intravascular injection, predictably result in toxic effects on the CNS (seizures, coma) and the heart (negative inotropy, conduction disturbances, arrhythmias). Table 27.2 lists commonly accepted maximum local anesthetic dosing for infiltration anesthesia.

Table 27.2 Maximum recommended dosing of local anesthetic agents for local infiltration

        b. Caution must be exercised in the performance of any invasive regional anesthesia procedure in the setting of ongoing or proposed anticoagulation or thrombolysis.

            Although regional anesthesia can be initiated without an apparent increase in the risk of bleeding in patients taking only aspirin or NSAIDs, The American Society of Regional Anesthesia and Pain Medicine (ASRA; www.ASRA.com) has recently updated their consensus recommendations for regional anesthesia in patients receiving antithrombotic therapy [14]. The group recommends holding the antiplatelet agents clopidogrel (Plavix) for 7 days, ticlopidine (Ticlid) for 14 days, and GP IIb/IIIa antagonists for 4 to 48 hrs before neuraxial block. ASRA also recommends holding the anticoagulant warfarin for 4 to 5 days, low molecular weight heparins for 12 to 24 hrs depending on drug and dose, and unfractionated heparin for 8 to 12 hrs depending on dosing interval, before neuraxial block placement. It should be noted that these same guidelines are recommended for consideration of deep plexus or peripheral nerve blockade in the setting of drug-altered hemostasis.

        c. Allergic reactions are not uncommon, particularly to the para-aminobenzoic acid metabolites of ester local anesthetics or to preservative materials in commercial local anesthetic preparations. True allergic reactions to preservative-free amide local anesthetics (e.g., lidocaine) are rare, and suspected cases are often attributed in retrospect to inadvertent intravascular injection of epinephrine-containing solutions.

        d. Concentration-dependent neurotoxicity of local anesthetics (e.g., cauda equina syndrome following IT local anesthetic injection) is now well described.

   E. a2-Adrenergic agonists

Clonidine is the prototypical drug in this class, although dexmedetomidine is also approved for clinical use. Both drugs produce analgesia through agonism at central α2-receptors in the substantia gelatinosa of the spinal cord and sedation through receptors in the locus coeruleus in the brainstem. They also may act at peripheral α2-receptors located on sympathetic nerve terminals to decrease norepinephrine output in sympathetically mediated pain. The analgesic effect of these drugs is distinct and complementary to that of opioids when used in combination. Clonidine may be administered orally to provide sedation and analgesia as a premedication. Preservative-free clonidine may be included as a component of epidural infusions or IT injections. Although these agents have limited respiratory depressant properties, hypotension, sedation, and dry mouth are common side effects from analgesic doses.

   F. Ketamine. Ketamine has complex interactions with a variety of receptors but is thought to act primarily through blockade of the excitatory effects of the neurotransmitter, glutamic acid, at the NMDA receptor in the CNS. It can be administered orally or parenterally to provide sedation, potent analgesia, and “dissociative anesthesia.” The principal advantages of ketamine stem from its sympathomimetic properties and lack of ventilatory depression. Cautions include increased secretions and dysphoric reactions. Ketamine administered by low-dose intravenous infusion as an adjunct to a post-sternotomy analgesic regimen may increase patient satisfaction and provide an opioid-sparing effect [15]. Ketamine may also be added as an adjunctive medication to epidural infusions, including thoracic epidural infusions for acute post-thoracotomy pain [16].

   G. Nonpharmacologic analgesia

     1. Cryoablation. A cryoprobe can be introduced into the intercostal space and used to produce transient (1 to 4 days) numbness in the distribution of the intercostal nerve. A cryoprobe circulates extremely cold gas on the order of –80°C. When applied for two to three treatments of approximately 2 min each, it temporarily disrupts neural function. Cryoablation has been shown to reduce pain and the need for systemic analgesics after lateral thoracotomy for cardiac surgery [17].

     2. Nursing care. Empathic nursing care and nursing-guided relaxation techniques are important components to patient comfort throughout the perioperative period and should not be overlooked [17].

III. Pain management strategies

   A. Oral. Gastrointestinal ileus is rarely a concern after routine cardiothoracic surgical procedures; therefore, transition to oral administration of analgesics should be considered as soon as pain management goals are likely to be effectively achieved by this route. This is particularly important because oral agents are currently the simplest, cheapest, and most reliable way to continue effective analgesia after hospital discharge, and they should be used as the mainstay of any “fast track” analgesia protocol.

   B. Subcutaneous/intramuscular. Subcutaneous (SC) and (IM) injections remain effective and inexpensive alternate parenteral routes to intravenous (IV) administration for delivery of potent systemic analgesia using opioids (e.g., morphine, hydromorphone, meperidine). SC or IM injection results in slower onset of analgesia than the IV route and, therefore, is more suitable for scheduled dosing (e.g., every 3 to 6 hrs) rather than “as needed.” A notable disadvantage of the SC route is injection-related discomfort, which can be largely avoided by slow injection through an indwelling SC butterfly needle.

   C. Intravenous. In the absence of neuraxial analgesia, IV opioid analgesia is generally the primary tool to provide effective pain relief for the early postoperative patient. The advantages of this route include rapid onset and ease of titration to effect. In addition, for the awake patient, patient-controlled IV delivery of opioids (i.e., patient-controlled analgesia [PCA]) has become widely available. PCA units combine options for baseline continuous infusion of drug with patient-administered bolus doses after programmed lockout periods to minimize risk of overdose and maximize the patient’s sense of “control” over their pain. Patient satisfaction using PCA analgesia rivals that with neuraxial analgesia.

   Analgesic agents that have traditionally been available only for oral administration are becoming available for parenteral usage. IV ketorolac and acetominophen have gained widespread acceptance as analgesic alternatives for thoracic surgical patients that are devoid of respiratory depressant effects.

   D. Interpleural. Interpleural analgesia involves placement of a catheter between the visceral and parietal pleura and subsequent instillation of local anesthetic solution. Ensuing pain relief is believed to be the result of blockade of intercostal nerves in addition to local actions on the pleura. Disadvantages of this technique include the requirement for relatively high doses of local anesthetic with relatively enhanced vascular uptake, poor effectiveness, and possible impairment of ipsilateral diaphragmatic function. For these reasons, interpleural analgesia has been largely abandoned as a strategy for pain control in cardiothoracic surgery patients.

   E. Intercostal. Sequential intercostal blocks (e.g., T-4 to T-10) can contribute to unilateral postoperative chest wall analgesia for thoracic surgery. Bilateral intercostal nerve blocks (ICB) may be used for pain relief after median sternotomy [18]. ICB requires depositing local anesthetic (e.g., 4 mL of 0.5% bupivacaine per nerve) at the inferior border of the associated rib near the proximal intercostal nerve. ICBs are generally performed through the skin before surgery or by the surgeon under direct vision within the chest. ICBs contribute to analgesia for up to 12 hrs, but in general they do not include blockade of the posterior and visceral rami of the intercostal nerve; therefore, they often require additional NSAID or parenteral analgesia to be effective.

   F. Paravertebral. Paravertebral blocks (PVBs) can provide unilateral chest wall analgesia for thoracic surgery. Sequential thoracic PVB injections (e.g., T-4 to T-10, 4 mL of 0.5% ropivacaine per level) may be combined with “light” general anesthesia for thoracotomy procedures and provide analgesia for several hours postoperatively. Anticipated chest tube insertion sites usually dictate the lowest PVB level required. Although use of PVBs reduces intraoperative opioid requirement, NSAID and/or opioid supplementation is often required after thoracotomy to achieve adequate comfort. “Emergence” from PVB-mediated analgesia may occur on the day after surgery, often after transfer from an intensive care environment; therefore, it is important that other analgesia alternatives be immediately available at this time. Advantages of PVBs and ICBs relative to neuraxial techniques include the avoidance of opioid side effects, risk of spinal hematoma, and hypotension related to bilateral sympathetic block. Nonetheless, disadvantages of ICB and PVB analgesia include that they are less reliable than thoracic epidural analgesia and can themselves be complicated by epidural spread of local anesthetic. Notably, compared to PVBs, ICBs do not affect the posterior and visceral ramus of the intercostal nerve and recede more rapidly. The paravertebral space, where peripheral nerves exit from the spinal canal, is limited superiorly and inferiorly by the heads of associated ribs, anteriorly by the parietal pleura, and posteriorly by the superior costotransverse ligament.

   G. Intrathecal. IT opioid analgesia is a suitable treatment for major pain after median sternotomy or thoracotomy [19]. The benefits and risks of a spinal procedure should always be carefully weighed before using this technique, particularly with regard to the risk of spinal hematoma in patients with abnormal hemostasis. Small-caliber noncutting spinal needles (e.g., 27-gauge Whitacre needle) are often selected for lumbar spinal injection of preservative-free morphine. Age rather than weight predicts proper IT opioid dosing in adults; 10 μg/kg IT morphine dosing is effective for cardiothoracic surgery in most adults, usually administered before induction of general anesthesia. Smaller doses (e.g., 0.3 to 0.5 mg, total dose) are required to reduce the likelihood of respiratory depression in elderly patients (older than 75 yrs). It is prudent to avoid the use of IT morphine in patients 85 years or older. Since rare patients will develop significant delayed respiratory depression, hourly monitoring of respiratory rate and consciousness for 18 to 24 hrs is mandatory with this technique. Reduced doses of sedative and hypnotic agents during general anesthesia are required to avoid excessive postoperative somnolence. Onset of thoracic analgesia is approximately 1 to 2 hrs after injection, lasting up to 24 hrs. Postoperative NSAID therapy complements IT morphine analgesia without sedative effects. IT clonidine (1 μg/kg) combined with IT morphine produces superior analgesia compared to either drug administered alone [20]. IV or oral analgesia must be immediately available in anticipation of the resolution of IT morphine analgesia approximately 24 hrs after injection because significant pain may develop rapidly. IT administration of other drugs for cardiac and thoracic surgery, such as local anesthetic agents or short-acting opioids (e.g., sufentanil), is mainly limited to the intraoperative period.

   H. Epidural. Epidural anesthesia is ideal for thoracic surgery and is the most widely studied and used form of regional analgesia for this purpose [5]. Although epidural catheter placement for use during and after cardiac surgery is reported to have benefits [21], this approach has not gained a similar level of acceptance.

   Thoracic epidural catheter location (T-4 to T-10) is generally preferred over lumbar for thoracic surgery. Proponents of thoracic catheter placement cite the reduced local anesthetic dosing requirements, closer proximity to thoracic segment dorsal horns, and reduced likelihood of dislodgement postoperatively. Concern regarding increased risk of spinal cord injury using a thoracic compared to a lumbar approach for epidural catheter placement has not been borne out; however, it is commonly recommended that thoracic epidural catheter placement occur while the patient is sufficiently alert to reliably report paresthesias or other complaints during the procedure. Selection of the thoracic interspace should be dictated by surgical site. The epidural catheter should be placed 4 to 6 cm into the epidural space and securely taped.

   Intraoperative use of an epidural catheter enhances the benefits of regional anesthesia for thoracotomy surgery by permitting a “light general” anesthetic technique with reduced residual respiratory depressant effects. Epidural local anesthetic block should be preceded by a “test dose” of epinephrine-containing local anesthetic to rule out intravascular or IT catheter placement. Epidural block can then proceed prior to incision, and administration of preincision epidural opioids may contribute to a pre-emptive analgesic effect. Epidural opioids should generally not be administered unless postoperative observation and monitoring for delayed respiratory depression is planned. To minimize postoperative somnolence and the risk of respiratory depression, administration of potent IV sedatives and opioids should be reduced or avoided during surgery, and agents used to maintain general anesthesia should be easily reversible (e.g., volatile anesthetic agents). Monitoring inhaled volatile anesthetic concentrations or using a bispectral analysis monitor to assess the level of consciousness may permit guided and reduced dosing of these sedative agents. A popular mixture for postoperative epidural analgesia is dilute local anesthetic (e.g., 0.125% bupivacaine) containing an opioid with intermediate lipid solubility properties (e.g., hydromorphone, 10 μg/mL); this is administered by continuous infusion at a starting rate of 4 to 7 mL/hr, ideally starting at least 15 min before the end of surgery and titrated to clinical effect. Since early titration of epidural analgesic infusions is often required and pain is not effectively reported by the awakening patient, an initial analgesic dose of hydromorphone and local anesthetic agent should be administered to the patient (e.g., a 200 μg IT hydromorphone bolus and 3 mL preservative-free 2% lidocaine) before emergence. IV ketorolac or acetominophen can also be administered at this time when indicated. Ketorolac is often especially effective in helping to manage shoulder discomfort secondary to indwelling thoracostomy tubes, since this complaint often persists in the setting of good incisional pain control with epidural analgesia alone. Titration of epidural analgesia to comfort should be completed in the postoperative recovery area where transfer of care to the acute pain care team should occur.


IV. Pain management regimens for specific cardiothoracic procedures

   A. Conventional coronary artery bypass and open chamber procedures. Over the past three decades, anesthetic design for cardiac surgery has commonly included large doses of potent opioids (e.g., fentanyl, sufentanil), thus assuring intraoperative hemodynamic stability and excellent analgesia but often requiring considerable periods of postoperative ventilation. Although this remains a useful approach for the management of selected high-risk patients, it has been recognized that most procedures are suitable for analgesia regimens compatible with more rapid recovery. Standard regimens for cardiac surgery currently include more modest intraoperative opioid dosing than in the past, with postoperative bedside availability of parenteral opioids as required in the first 12 to 24 hrs, either patient-controlled or administered by a nurse. Transition to oral agents is encouraged as soon as food is tolerated.

   The move away from traditional high-dose opioid anesthesia has increased interest in different approaches to analgesia after cardiac surgery. Routine NSAID therapy for uncomplicated patients is a safe and cost-effective way to complement opioid analgesia. Preoperative IT morphine has gained popularity in some centers. In experienced hands, imaginative combinations such as preoperative IT morphine and intraoperative IV remifentanil infusion provide reproducible excellent analgesia, with tracheal extubation often possible in the operating room [18].

   B. Off-pump (sternotomy) cardiac procedures. One interpretation of “minimally invasive” cardiac surgery involves the avoidance of cardiopulmonary bypass (CPB). Whether outcomes from off-pump are equivalent, superior, or inferior to on-pump surgery for coronary artery disease remains to be answered; however, these procedures are common. Theoretically, avoidance of CPB with off-pump procedures may reduce the systemic inflammatory response associated with surgery and ironically increase the perception of pain. Practically, with the introduction of a “fast track” approach that has accompanied off-pump cardiac surgery, standard analgesia regimens are challenged, and inadequate pain relief has become a more common reason for delayed hospital discharge than in the past. Interest in analgesic approaches other than parenteral opioids has paralleled that for the patients undergoing traditional cardiac surgery with CPB, as outlined above (see Section IV.A). Because reduced heparin administration and avoidance of CPB-related impairment of hemostasis are part of off-pump surgery, IT morphine, oral NSAID therapy, and even interpleural local anesthetic regimens are being tried as analgesia strategies, and new approaches may ultimately gain approval in this patient group.

   C. Minimally invasive (minithoracotomy/para- or partial sternotomy/robotic) cardiac procedures. In contrast to off-pump procedures, a second interpretation of “minimally invasive” cardiac surgery involves port-access catheter-based CPB employing very small incisions to achieve surgical goals. Although early hopes were that port-access procedures would be associated with less pain, this has not been proven to be true, most likely because of the relocation of the smaller incisions to more pain-sensitive areas (e.g., minithoracotomy). In addition to the alternate analgesic approaches outlined for patients undergoing traditional cardiac surgery with CPB (see Section IV.A), the possibility of using novel approaches to minithoracotomy analgesia including ICBs, one-shot PVBs, and PVB by continuous infusion exists but has not been explored sufficiently to recommend these approaches.


   D. Thoracotomy/thoracoscopy procedures (noncardiac). An increasing number of the patients presenting for lung surgery have end-stage lung disease and would not have been considered eligible for an operative procedure several years ago [22]. In part, these changes in eligible candidates for lung resection are due in part to the introduction of less invasive techniques including minimally invasive video-assisted thoracic surgical (VATS) procedures. Patients with severe lung disease have the most to gain in terms of improved outcome from optimal postoperative analgesia (e.g., continuous thoracic epidural) [22]. As the potential of VATS is being realized, more physiologically invasive procedures (e.g., lobectomy) are now routinely performed using VATS approaches. Finally, some procedures (e.g., pneumonectomy) still require the traditional and more painful thoracotomy incision.

   “Light” general anesthesia with regional blockade of the chest wall is a particularly suitable anesthetic approach for lung and other chest surgery. Sedatives (e.g., midazolam) should be used sparingly throughout; often a small dose of midazolam (e.g., 0.5 mg) will extend the actions of shorter-acting sedatives such as propofol (e.g., 10 mg) for line placement. Using this technique, residual sedative/hypnotic effects can be minimized, early tracheal extubation reliably achieved, and the transition to postoperative pain management facilitated.

   Analgesia for VATS and thoracotomy procedures in the intraoperative and postoperative period is often achieved through a multimodal approach including parenteral opioids, NSAIDs, and regional anesthesia. A spectrum of regional anesthesia procedures are available including thoracic epidural, spinal, paravertebral, intercostal, and interpleural blocks. These can be performed transcutaneously by the anesthesiologists or in some cases from within the rib cage during surgery by the surgeon. Options include one-shot injections or catheters tunneled under the parietal pleura that can be left in place for infusions of local anesthetic and/or opioid. Selection of a regional analgesia approach should include a plan for transition to oral medication and be matched to the expected hospital discharge timing; neuraxial opioids may delay discharge if given inappropriately. Many patients with normal pulmonary function having a minor surgical procedure will have good analgesia with IV PCA morphine or fentanyl alone.

   Selection of regional blockade technique is best made after evaluation of both patient status and the demands of the surgery. American Society of Anesthesiologists class I to II patients anticipating postoperative hospital stays up to 48 hrs may benefit from single-shot local anesthetic blocks (e.g., PVBs and ICBs); however, anxious patients in this group should not be overly pressured to undergo a regional procedure. In contrast, patients who are deconditioned or undergoing more extensive procedures are more likely to benefit from regional anesthesia and placement of a thoracic epidural catheter unless contraindicated. Routine postoperative NSAID or acetominophen therapy should be considered, since these agents are devoid of sedation and are particularly effective analgesics in combination with regional analgesia. Local anesthetic/opioid mixtures are popular analgesic regimens for use as continuous epidural infusions (see Section III.H). However, in high-risk cases (e.g., lung volume reduction or lung transplant surgery) where avoidance of all respiratory depressants is desirable, analgesia can be achieved using a dilute local anesthetic agent alone. Tachyphylaxis is a common problem with any local anesthetic-alone technique requiring frequent rate readjustments. Removal of an epidural catheter subjects a patient to all the same risks as insertion. When transfer from epidural to oral analgesia is being considered, thromboprophylaxis protocols should be coordinated with epidural catheter removal to minimize the risk of epidural hematoma. If the patient is taking warfarin, the international normalized ratio at the time of catheter removal should be <1.5 to minimize the risk of bleeding.

   E. Open and closed (total endovascular aortic repair [TEVAR]) descending thoracic aortic procedures. Major surgical procedures to treat the disease of the descending thoracic aorta often require both an extensive left thoracotomy incision and a long midline abdominal incision. Unfortunately, serious complications are common with these procedures and include high incidences of bleeding/coagulopathy due to the extensive surgery, paraplegia from spinal cord ischemia, and acute kidney injury. Despite the extent and pain associated with these incisions, analgesia is often relegated to a secondary concern. In addition, increased risks of renal and spinal cord injury are relative contraindications to some of the most useful agents of a multimodal approach to severe postoperative pain. However, some creative approaches to analgesia are being considered. In addition to standard intravenous opioid techniques, a tunneled catheter under the left parietal pleura can be placed to extend cephalad over several dermatomes of the chest wall and deliver dilute local anesthetic. Unfortunately, there is little research in this area to guide clinicians. Some anesthesiologists and surgical teams even feel that the benefits of thoracic epidural analgesia merit placement of a thoracic epidural catheter either preoperatively or after surgery. Finally, it is likely that more patients will present for descending thoracic aortic procedures in the future as endovascular stent-grafting techniques improve. Fortunately, these latter procedures are minimally invasive, rarely involve more than groin incisions for access to the femoral vessels and should not be associated with severe pain.

V. Approach to specific complications and side effects of analgesic strategies

   A. Complications of nonsteroidal anti-inflammatory drugs

     1. Renal toxicity. Normal patients exhibit a low rate of prostaglandin synthesis in the renal vasculature, such that cyclo-oxygenase inhibition has little effect. However, vasodilatory prostaglandins may play an important role in preservation of renal perfusion in disease states. Nephrotoxicity, secondary to vasoconstriction of both afferent and efferent renal arterioles leading to reduced glomerular filtration rate, is commonly seen with NSAID administration in patients with dehydration, sepsis, congestive heart failure, or other causes of renal hypoperfusion. Avoiding NSAID-induced renal toxicity is best accomplished by limiting or avoiding their use in patients with decreased renal reserve and in those at risk for hypoperfusion. Risk appears to be low with perioperative ketorolac administration (1 : 1,000 to 1 : 10,000) [23]. NSAID-induced nephrotoxicity is usually reversible with discontinuation of the drug.


     2. Gastrointestinal mucosal irritation. Gastrointestinal mucosal irritation is the most common NSAID side effect. It can occur regardless of route of administration. It may result in erosion and severe gastrointestinal bleeding. Prostaglandins are involved in multiple aspects of gastric mucosal protection, including mucosal blood flow, epithelial cell growth, and surface mucus and bicarbonate production. Prophylaxis may involve administration of histamine (H2) receptor antagonists, proton pump inhibitors (omeprazole), protective agents (sucralfate), or prostaglandin analogs (misoprostol). Each of these treatments appears to be effective in decreasing ulceration with NSAID treatment.

     3. Impaired primary hemostasis. Nonspecific cyclo-oxygenase inhibition leads to impaired platelet aggregation. It may increase intraoperative or postoperative bleeding. Duration of effect is highly variable depending on individual drug (reversible vs. irreversible enzymatic inhibition). The only effective prophylaxis or treatment is to discontinue NSAIDs for a sufficient duration preoperatively (ibuprofen more than 3 days, aspirin more than 7 to 10 days).

   B. Nausea and vomiting. Nausea and vomiting as a consequence of analgesia is most commonly associated with opioids. Opioids cause nausea primarily through activation of the chemoreceptor trigger zone of the brainstem in the floor of the fourth ventricle. A vestibular component is also postulated because it is clear that motion increases the incidence of nausea. Finally, the inhibitory effects of opioids on gastrointestinal motility may contribute. Nausea can accompany opioid therapy regardless of the route of administration. It occurs in roughly 25% to 35% of patients treated with spinal opioids and is more frequent with spinal use of hydrophilic drugs (e.g., morphine) secondary to enhanced rostral spread of these agents [24].

   Treatment can include traditional antiemetic drugs such as prochlorperazine, chlorpromazine, promethazine, metoclopramide, or dexamethasone. However, many of these treatments can be complicated by excessive sedation and/or extrapyramidal side effects secondary to central dopamine receptor antagonism. In contrast, serotonin (5-HT) receptor type 3 antagonists are effective antiemetics with fewer side effects. A range of 5-HT3 antagonists with differing half-lives are available or being studied, including ondansetron (4 to 6 hrs), granisetron (5 to 8 hrs), dolasetron (7 hrs), and palonosetron (40 hrs). Scopolamine, administered via transdermal patch to deliver 0.5 mg/day, is an effective antiemetic for spinal opioids. IV naloxone in doses up to 5 μg/kg/hr is extremely effective in reversing nausea from spinal opioids, without apparent antagonism of analgesia. Often, however, such symptomatic treatment is effective in reducing, but not eliminating, nausea.

   C. Pruritus. Pruritus is a common side effect of opioids administered by any route, but it can be particularly problematic after central neuraxial administration. The mechanism is unclear and likely complex, but pruritis is not likely caused solely by either preservatives within the opioid preparation or histamine release. Pruritus often improves as the duration of opioid treatment lengthens. Pruritus is most effectively treated with antihistamines, mixed agonist–antagonist opioids such as nalbuphine, or by naloxone infusion as outlined above.


   D. Respiratory depression. Hypoventilation is a potentially life-threatening complication of opioids. It can occur early after administration by any route, but it is particularly feared as a delayed complication of neuraxial opioid administration. Whatever the method of administration, opioid-related hypoventilation occurs secondary to elevated cerebrospinal fluid drug levels with depression of the medullary respiratory center, either from systemic absorption or rostral spread of neuraxially administered drug. Respiratory depression requiring naloxone administration is reported to occur in 0.2% to 1% of patients receiving epidural narcotics [25], but the incidence is likely higher in opioid-naive patients being treated for acute pain. Other factors that may increase the risk include advanced age, poor overall medical condition, higher narcotic dosing (particularly of hydrophilic drugs), increased intrathoracic or intra-abdominal pressure (as may occur during mechanical ventilation), and coincident administration of other CNS depressants. Patients who have received spinal narcotics in the prior 18 to 24 hrs or in whom continuous infusions are being administered should have their ventilatory rate and level of alertness confirmed at least hourly. Caretakers should be aware that deteriorating levels of consciousness might portend severe respiratory depression even if ventilatory rates appear preserved. Arterial blood gas analysis should be used early in the investigation of decreased alertness. Modest doses of naloxone (0.04 to 0.1 mg IV) are usually sufficient to temporarily reverse respiratory depression if discovered before it has become severe.

   E. Neurologic complications. Although neurologic complications from analgesic procedures are extremely rare, when these occur they can be catastrophic, and appropriate management is key to minimizing adverse consequences. Nerve injury may be heralded by an acute discomfort with nerve trauma during a procedure but may only be apparent when local anesthetic effects recede. Therefore, it is essential that this diagnosis is not overlooked in the evaluation of a prolonged block. In particular, if a spinal cord hematoma is being considered, it should be remembered that the promptness of surgical decompression of a spinal hematoma is the most important predictor of recovery of neurologic function [26]. Eighty-eight percent of neurologic deficits related to spinal hematoma will resolve if surgical decompression occurs within 12 hrs of symptom onset, whereas only 40% will have improvement when surgery occurs beyond 24 hrs. A key aspect in evaluation of a possible nerve injury is the involvement of a neurologist in consultation. Most nerve injuries are transient and recover over several days, but the opinion of a specialist in this area will assure that effective acute treatments are not delayed.

VI. Risk versus benefit: Epidural/intrathecal analgesia for cardiac surgical procedures requiring systemic anticoagulation

Controversy has surrounded the subject of whether the risks of neuraxial blockade (principally, epidural hematoma or other spinal bleeding) outweigh the potential benefits (principally, reduced postoperative myocardial ischemia and infarction) in patients undergoing cardiac surgery requiring systemic anticoagulation. Clearly, extensive clinical experience and literature support the safety of neuraxial procedures in the setting of heparin anticoagulation accompanying major vascular surgery; but, in these cases, heparin is typically administered in doses smaller than for cardiac surgery, and its anticoagulant effects are not compounded by the consumptive coagulopathy, inflammatory response, and fibrinolysis that sometimes accompany CPB. For some time, the pro/con debate seemed to favor the safety of neuraxial blockade, provided that commonly recommended precautions are followed. These precautions include avoiding such procedures in patients with any pre-existing hemostatic disorder, postponing cardiac surgery for at least 24 hrs in the event of a traumatic (“bloody”) tap at the time of needle or catheter insertion, and delaying heparin administration for at least 60 min after performance of an uncomplicated neuraxial procedure. These beliefs were supported by an oft-cited mathematical analysis published in 2000 suggesting that the risk of spinal bleeding was likely acceptable given the postulated benefits [27]. Up until this time, there were no published reports of epidural hematoma complicating thoracic epidural anesthesia/analgesia for cardiac surgery. The ASRA consensus guidelines only indicate that “insufficient data and experience are available to determine if the risk of neuraxial hematoma is increased when combining neuraxial techniques with the full anticoagulation of cardiac surgery” [14].

Since 2000, however, a body of literature has assembled that does not support the belief that central neuraxial analgesia improves important clinical outcome [8]. Outcome after cardiac surgery rests on many factors, and it may well be that influences such as quality of the surgical intervention and the extent of major organ dysfunction after surgery (factors largely outside the anesthesiologist’s control) outweigh the importance of quality analgesia on major morbidity or mortality. Also, in 2004, the first published report of epidural hematoma complicating thoracic epidural placement for cardiac surgery appeared [28], and several other such bleeding complications have occurred in the United States since 2000. It is still true that no reports exist of spinal bleeding complicating single-shot IT drug placement prior to cardiac surgery, and the risk for epidural cathether insertion prior to cardiac surgery has been assessed to be equivalent to that for obstetric anesthesia [29].

Despite widespread belief in the salutatory effects of excellent analgesia, the principal patient-related benefit of central neuraxial analgesia for cardiac surgery is patient satisfaction. Additional benefits of epidural or IT analgesia are not supported by the literature. Pending additional contributions to our understanding, the trend in expert opinion has recently shifted to argue for caution, particularly regarding thoracic epidural catheter placement prior to “full” heparinization for cardiac surgery.


VII. Considerations in facilitating transitions of care

Reliable postoperative analgesia is a key component in facilitating prompt tracheal extubation (within 6 hrs) after cardiac surgery. Such “fast tracking” of low-risk cardiac surgery patients appears to be safe and has been adopted by many centers throughout the world as a process to decrease intensive care unit and hospital lengths of stay. Patients may receive additional benefits such as improved cardiac function and reduced rates of respiratory infections and complications. Attention to reducing risk and to institutional resource utilization has expanded the scale of attention for speeding and improving transitions of care to all cardiothoracic surgical patients, not just those deemed “low risk” in advance. Similarly, the role of the anesthesiologist in care pathway design has expanded well beyond facilitating early extubation and early postoperative analgesia, toward greater preoperative and postoperative integration as a key perioperative physician [30].

IT morphine is used in many centers for eligible cardiac surgery patients to provide analgesia and mild sedation in the early postoperative period. However, some studies have failed to demonstrate a beneficial effect of IT morphine either in improving early analgesia or in facilitating early extubation. NSAIDs complement opioid analgesia regardless of how the opioid is administered. Indomethacin, administered rectally as 100-mg suppositories, is a common component of fast-tracking protocols for cardiac surgery aimed at reducing pain and early postoperative narcotic use. Some NSAIDs may antagonize opioid-induced respiratory depression [31]. Intraoperative and postoperative continuous infusions of remifentanil or alfentanil (with or without supplemental propofol infusion) are used in some centers to allow controlled analgesia and “scheduled extubation.” Both a high-dose narcotic technique using the ultra-short-acting narcotic remifentanil [18] or an anesthetic incorporating high thoracic epidural conduction block [21] have been suggested as good methods that may improve outcome through inhibition of perioperative stress response while facilitating early extubation and fast tracking.

Postoperative analgesia strategy for thoracic surgery patients often influences disposition when continuous epidural infusions are used, since the care team must be equipped and trained to intervene when potentially serious complications of postoperative analgesia occur such as hypotension from local anesthetic-mediated reductions in sympathetic tone and delayed respiratory depression due to cephalad spread of neuraxial opioids. In formulating an analgesia plan for thoracic surgery, considerable respect must be paid to failure to achieve tracheal extubation—a serious complication of emergence whose occurrence is partly under the influence of the anesthesiologist. This is particularly important since major pulmonary complications of lung resection surgery are more than twice as likely in the setting of postoperative respiratory failure and highly associated with other markers of adverse outcome, including postoperative mortality. Contributors to the heightened risk of respiratory failure after lung resection include “variable” factors amenable to optimization such as inadequate respiratory mechanics from pain-related chest wall splinting, poor positioning, and residual paralysis.

Since pain at emergence from anesthesia for lung resection is extremely difficult to treat without increasing the risk of acute respiratory depression and interfering with efforts to extubate the patient, the anesthesiologist must be confident that analgesia is established pre-emergence. If a thoracic epidural catheter has been placed, a common practice 10 to 15 min prior to emergence is to supplement existing analgesia with an additional 2 mL bolus of 2% preservative-free lidocaine for an average adult male; this represents a modest investment in protection from emergence pain that rarely causes block-mediated hypotension but allows tracheal extubation before more pain management interventions are needed. Fortunately, difficult emergence sequences are relatively infrequent, but the patient with limited respiratory reserve likely has the most to gain from an experienced anesthesia team to avoid a prolonged episode of postoperative mechanical ventilation. Rarely, sequential blood gas determinations immediately following tracheal extubation (e.g., every 3 min) identify the marginal patient whose CO2 levels are rising despite optimal analgesia, a concerning finding that requires further prompt intervention and optimization to avert respiratory failure and tracheal reintubation.


 1. Lui F, Ng KF. Adjuvant analgesics in acute pain. Expert Opin Pharmacother. 2011;12(suppl 3):363–385.

 2. Brame AL, Singer M. Stressing the obvious? An allostatic look at critical illness. Crit Care Med. 2010;38(suppl 10):S600–S607.

 3. Svircevic V, van Dijk D, Nierich AP, et al. Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery. Anesthesiology. 2011;114(suppl 2):271–282.

 4. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg. 2007;104(suppl 3):689–702.

 5. Manion SC, Brennan TJ. Thoracic epidural analgesia and acute pain management. Anesthesiology. 2011;115(suppl 1):181–188.

 6. Gottschalk A, Cohen SP, Yang S, et al. Preventing and treating pain after thoracic surgery. Anesthesiology. 2006;104(suppl 3): 594–600.

 7. Dowling R, Thielmeier K, Ghaly A, et al. Improved pain control after cardiac surgery: results of a randomized, double-blind, clinical trial. J Thorac Cardiovasc Surg. 2003;126(suppl 5):1271–1278.

 8. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis. Anesthesiology. 2004;101(suppl 1):153–161.

 9. Svircevic V, Nierich AP, Moons KG, et al. Thoracic epidural anesthesia for cardiac surgery: a randomized trial. Anesthesiology. 2011;114(suppl 2):262–270.

10. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18(suppl 4):S3–S13.

11. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352(suppl 11):1081–1091.

12. Sinatra RS, Jahr JS, Reynolds LW, et al. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102(suppl 4):822–831.

13. Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth.2005;19(suppl 3):306–309.

14. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35(suppl 1):64–101.

15. Lahtinen P, Kokki H, Hakala T, et al. S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery. Anesth Analg. 2004;99(suppl 5):1295–1301; table of contents.

16. Ryu HG, Lee CJ, Kim YT, et al. Preemptive low-dose epidural ketamine for preventing chronic postthoracotomy pain: a prospective, double-blinded, randomized, clinical trial. Clin J Pain.2011;27(suppl 4):304–308.

17. Oates HB. Non-pharmacologic pain control for the CABG patient. Dimens Crit Care Nurs. 1993;12(suppl 6):296–304.

18. Zarate E, Latham P, White PF, et al. Fast-track cardiac anesthesia: use of remifentanil combined with intrathecal morphine as an alternative to sufentanil during desflurane anesthesia. Anesth Analg.2000;91(suppl 2):283–287.

19. Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg. 2005;101(suppl 5): S30–S43.

20. Lena P, Balarac N, Arnulf JJ, et al. Intrathecal morphine and clonidine for coronary artery bypass grafting. Br J Anaesth. 2003;90(suppl 3):300–303.

21. Scott NB, Turfrey DJ, Ray DA, et al. A prospective randomized study of the potential benefits of thoracic epidural anesthesia and analgesia in patients undergoing coronary artery bypass grafting. Anesth Analg.2001;93(suppl 3):528–535.

22. Licker MJ, Widikker I, Robert J, et al. Operative mortality and respiratory complications after lung resection for cancer: impact of chronic obstructive pulmonary disease and time trends. Ann Thorac Surg. 2006;81(suppl 5):1830–1837.

23. Myles PS, Power I. Does ketorolac cause postoperative renal failure: how do we assess the evidence? Br J Anaesth. 1998;80(suppl 4): 420–421.

24. Carr DB, Cousins MJ. Spinal route of analgesia: opioids and future options for spinal analgesic chemo therapy. In: Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh P, eds. Cousins & Bridenbaugh’s Neural Blockade in Clinical Anesthesia and Pain Medicine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:899.

25. Ready L. Regional anesthesia with intraspinal opioids. In: Loeser J, ed. Bonica’s Management of Pain. Philadelphia, PA: Lippincott, Williams & Wilkins; 2001:1953–1966.

26. Kunz U. Spinal hematoma: a literature survey with meta-analysis of 613 patients. Neurosurg Rev. 2003;26(suppl 1):52.

27. Ho AM, Chung DC, Joynt GM. Neuraxial blockade and hematoma in cardiac surgery: estimating the risk of a rare adverse event that has not (yet) occurred. Chest. 2000;117(suppl 2):551–555.

28. Rosen DA, Hawkinberry DW 2nd, Rosen KR, et al. An epidural hematoma in an adolescent patient after cardiac surgery. Anesth Analg. 2004;98(suppl 4):966–969.

29. Bracco D, Hemmerling T. Epidural analgesia in cardiac surgery: an updated risk assessment. Heart Surg Forum. 2007;10(suppl 4): E334–E337.

30. White PF, Kehlet H, Neal JM, et al. The role of the anesthesiologist in fast-track surgery: from multimodal analgesia to perioperative medical care. Anesth Analg. 2007;104(suppl 6):1380–1396, table of contents.

31. Moren J, Francois T, Blanloeil Y, et al. The effects of a nonsteroidal antiinflammatory drug (ketoprofen) on morphine respiratory depression: a double-blind, randomized study in volunteers. Anesth Analg. 1997;85(suppl 2):400–405.