1. 1. 1 CHAPTER 1 POSTOPERATIVE ANALGESIA FOR THORACOTOMY PATIENTS: A CURRENT REVIEW PETER H. NORMAN, MD, FRCPC M. DENISE DALEY, MD, FRCPC ALICIA KOWALSKI, MD It is natural to want to relieve pain and suffering. None are more aware of this than those professionals who have devoted their lives to the provision of anesthesia, yet we have often been prevented from alleviating pain by not understanding its pathogenesis or by a lack of appropriate tools to deal with it. Intraoperative pain is now only of historic concern. It is our fervent hope that postoperative pain will follow intraoperative pain into the history books. Not so long ago, certainly within the professional experience of some of us, a minimalist approach was taken to the management of pain after thoracic surgery. Anesthesiology residents and faculty alike were admon- ished to keep total opioid dosage low so the patient would want to breathe after surgery. During this era, the classic thoracotomy patient would be nearly apneic from pain in the postanesthesia care unit. Hypoxic and hypercarbic, diaphoretic and hypertensive, patients would gradually improve to the point at which they could actually breathe and complain of pain only after large doses of opioids. Frequent arterial blood gas analy- ses often demonstrated the unusual observation that the administration of opioids led to a decrease in carbon dioxide tension and an increase in oxygen tension in this setting. In 1973 Gibbons and colleagues suggested that thoracic epidural blockade was the treatment of choice for relief of pain after a chest injury.1 The major limitation was sympathetic blockade causing hypotension. To prevent this complication, they advocated intercostal blockade for fractures at or above the fifth rib. The modern era of pain management after thoracic surgery began with the introduction of epidural narcotic tech- niques for post-thoracotomy pain.2,3 Soon continuous infusions were advocated,4 and the effect of better postop- erative analgesia on pulmonary function was investigated.5 This led to an increased ability to control post-thoraco- tomy pain and also stimulated the overall interest in find- ing other useful modalities for post-thoracotomy pain relief. Older or abandoned techniques were investigated with renewed interest and used singly or in combinations. For at least the past 10 years, the immediate postopera- tive pain of most thoracotomy patients has been well handled. There are occasional patients whose pain is diffi- cult to manage because of coexisting disease processes that contraindicate epidural analgesia, anatomic factors, and/or pre-existing chronic pain, but currently there are techniques to help even these patients. As an uninten- tional consequence of relieving the severe, acute incisional pain of surgery, we may have unmasked other sources of equally troubling pain such as referred pain and sympa- thetically mediated pain. Much research is focused on treating these new modalities. This unbundling of post- operative pain has been termed disaggregation.6 Another area of increasing interest is the pathogenesis of chronic postoperative pain. Whether we can affect or even prevent this unhappy outcome remains to be seen. Post-Thoracotomy Pain Acute Pain Pain in the first few weeks after a thoracotomy arises from a variety of different mechanisms. The best charac- terized mechanism is somatic pain, which is localized to the area around the incision and chest tube insertion
2. 2. sites. It is produced by direct injury to the skin and underlying subcutaneous tissues, fasciae, ligaments, muscles, and ribs. Damaged tissue releases a variety of algesic substances, including substance P, prostaglandins, and serotonin, which stimulate the peripheral nerve endings.7 Intercostal nerves from the area conduct these pain impulses to the spinal cord and thence to the brain via the spinothalamic and spinoreticular tracts. Somatic pain is responsible for the sharp, severe postoperative pain that is exacerbated by movement and is believed to be primarily mediated by type A delta nerve fibers.8 Visceral, or nonincisional, pain is responsible for the dull, nauseating, diffuse thoracic wall aching sensation expe- rienced after a thoracotomy. It is mediated by type C nerve fibers, which travel with the autonomic nerves. Both the vagus and sympathetic nerves probably contribute to this type of pain.8 Another form of pain frequently reported in post- thoracotomy patients is localized to the ipsilateral shoul- der region. Although it is often moderate to severe in intensity and present in 75 to 85% of patients who have had a thoracotomy,911 this type of pain has received little attention in the literature. It has been attributed to a vari- ety of factors, including distraction of the posterior thoracic ligaments or shoulder joint due to patient posi- tioning; stretching of the brachial plexus, also as a conse- quence of intraoperative positioning; transection of a major bronchus; and referred pain from the phrenic nerve.9 As the latter provides sensory innervation to the pericardium and pleura, mechanical trauma to these regions during surgery and irritation of the pleural surfaces by chest tubes postoperatively can result in phrenic nerve stimulation, with referral to the shoulder. Scawn and colleagues have demonstrated a reduction in the incidence of post-thoracotomy shoulder pain from 85 to 33% with the injection of 10 mL of 1% lidocaine into the periphrenic fat at the level of the diaphragm.9 In this same study, there was a small but insignificant increase in arterial partial pressure of carbon dioxide (PaCO2) in the first 2 postoperative hours in patients receiving a phrenic nerve block, thereby suggesting the possibility of diaphragmatic paresis. The technique may thus be inappropriate in patients with severely compro- mised respiratory function. The lack of efficacy of supras- capular nerve blockade in relieving post-thoracotomy shoulder pain demonstrated by Tan and colleagues provides further evidence that distraction of the shoulder joint does not play a major role in the generation of this type of pain.11 The extent to which the surgical approach contributes to the severity of post-thoracotomy pain is unclear. Anteroaxillary and anterior limited thoracotomies are less painful procedures than are posterolateral thoraco- tomies.12,13 When muscle-sparing thoracotomies have been compared with traditional posterolateral thoraco- tomies (involving a transection of the latissimus dorsi muscle), some studies have demonstrated less postopera- tive pain with the former,14 whereas others have revealed no difference between the two techniques.15,16 It is well appreciated that thoracoscopic procedures result in less pain than do traditional thoracotomies in the early post- operative period, but Nomori and colleagues have demonstrated this benefit to be lost by 14 days after surgery.17 The lack of a consistent and/or persistent decrease in post-thoracotomy pain with less extensive surgical incisions provides further evidence that the actual surgical incision is just one of several mechanisms responsible for post-thoracotomy pain. Chronic Pain Post-thoracotomy pain syndrome is defined as pain that recurs or persists along a thoracotomy scar at least two months following the surgical procedure.18 There is usually tenderness, sensory loss, and absence of sweating along the thoracotomy scar.18 The incidence is variable, ranging from 2 to 67%.19 Dajczman and colleagues stud- ied 59 of 206 sequential patients who had undergone a unilateral thoracotomy; all procedures were performed by one surgeon over a period of 5 years.20 Thirty to 73% of the patients available for evaluation were experiencing pain (Table 1-1), which most rated at a visual analog scale (VAS) of two to four (Figure 1-1). These results were confirmed by Perttunen and colleagues,21 who found an incidence of post-thoracotomy pain of 80% at 3 months, 75% at 6 months, and 61% after 1 year. More than 50% of these patients had limitations of their activities of daily living imposed by the chronic pain. There was also a 3 to 5% incidence of severe pain. Intriguingly, early consumption of larger quantities of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased incidence of long-term prob- lems. As suggested by Perttunen and colleagues, this could 2 / Advanced Therapy in Thoracic Surgery TABLE 1-1. Frequency of Post-Thoracotomy Pain at Various Intervals following Surgery Time since No. of Total No. of Percentage of Thoracotomy Patients Patients Evaluable (yr) with Pain Evaluable Patients with Pain 1* 6 12 50 12 11 15 73 23 7 13 54 34 3 6 50 45 3 10 30 Total 30 56 Adapted from Dajczman E et al.20 *At least 2 months post-thoracotomy.
3. 3. imply that patients with more severe acute postoperative pain have a greater likelihood of developing chronic pain; alternatively, it may just imply that patients with a lower pain threshold are more likely to develop chronic pain. A study by Katz and colleagues also suggested that increased postoperative pain intensity at 24 and 48 hours predicted the later development of chronic pain.22 Better pain relief may not be the only factor and, in fact, may negatively affect outcome. Although the study was only carried out to 12 days, Nomori and colleagues found that continuing epidural analgesia beyond 3 postoperative days led to a rebound increase in pain when the epidural was removed, such that the prolonged epidural group had more pain on postoperative days 8 and 9.23 Video-assisted thoracotomy is not a panacea. Although the acute pain experienced is less, the pain still present from video-assisted thoracotomy after 1 year (Tables 1-2 and 1-3) is indistinguishable from that result- ing from conventional thoracotomy.24 Much work remains to be done, and it is not possible to predict whether any analgesic approach or combina- tion of approaches will lessen the development of post- thoracotomy pain syndrome. Systemic Analgesia Opioids Opioids have been the mainstay of pain relief for thou- sands of years but were restricted to oral or inhalation use until the invention of hollow needles by Alexander Wood in 1853. Intravenous use was employed only in the operating room until the development of syringe pumps and patient-controlled systems, giving rise to patient- controlled analgesia (PCA). From its modest beginnings, PCA has evolved from a specialized tool of pain special- ists into a routine modality employed by any surgeon. PCA has also allowed the use of shorter-acting agents that must be given by continuous infusion owing to their evanescent action, such as fentanyl, sufentanil, and remifentanil. Because of the extreme potency of the latter, it should probably be restricted to perioperative use by an anesthesia provider. Oral opioids are still very much a part of perioperative analgesia because most patients are discharged on them and then maintained on them for months. The past 10 years has seen a decreasing reluctance to employ stronger opioids such as oxycodone, hydromorphone, and methadone out of hospital. Typical conversion ratios are given in Table 1-4. Some novel delivery systems should be mentioned. Highly lipid-soluble opioids may be absorbed directly across the skin or mucous membranes. Currently only fentanyl is used for direct transfer across the skin (Duragesic, Alza Corporation, Palo Alto, CA). Through the incorporation of a rate-limiting membrane, the Postoperative Analgesia for Thoracotomy Patients: A Current Review / 3 FIGURE 1-1. The distribution of visual analog scale (VAS) scores among patients reporting pain. Most patients chose a VAS of four or less. Reproduced with permission from Dajczman E et al.20 0 2 4 6 8 10 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 VAS NumberofPatients TABLE 1-2. Chronic Postoperative Pain Dysfunction Less Than 1 Year after VATS or Conventional Thoracotomy VATS Thoracotomy p Value Pain 30% 44% .03 Pain scale (05) 1.2 2.2 .01 Pain treatment 11% 18% NS Function 10% 26% .001 Adapted from Landreneau RJ et al.24 NS = not significant; VATS = video-assisted thoracic surgery. TABLE 1-3. Chronic Postoperative Pain/Dysfunction More Than 1 Year after VATS or Conventional Thoracotomy VATS Thoracotomy p Value Pain 22% 29% NS Pain scale (05) 1.0 1.7 NS Pain treatment 6% 16% NS Function 14% 15% NS Adapted from Landreneau RJ et al.24 NS = not significant; VATS = video-assisted thoracic surgery. TABLE 1-4. Conversion Table for Opioids* Opioid IV/SQ Opioid to IV/SQ Morphine IV/SQ Morphine to IV/SQ Opioid Oral Opioid to Oral Morphine Oral Morphine to Oral Opioid Hydromorphone 5 0.2 5 0.2 Meperidine 0.13 8 0.1 10 Oxycodone 1.5 0.7 Hydrocodone 0.5 2 Adapted with permission from Cancer Pain Guideline: M. D. Anderson Cancer Center internal document, 1994. *Oral morphine to intravenous/subcutaneous (IV/SQ) morphine, divide by 3; IV/SC morphine to oral morphine, multiply by 3.
4. 4. influence of the variable permeability of the skin is decreased. Nevertheless, there is a significant variability in the systemic drug levels and analgesic effects. As well, there is an accumulation of fentanyl under the patch, providing appreciable serum levels for up to 24 hours after patch removal.25 Because of the possibility of apnea owing to high serum levels in opioid-naive patients,26 transdermal fentanyl is not currently recommended for acute postoperative pain. One approach that may permit its use in the future is to combine a low-dose transder- mal fentanyl patch with an NSAID.27 Another possibility is to add electrical control to enhance the rate of fentanyl absorption across the skin. This iontophoretic route of administration is currently experimental but may offer the possibility of patient-controlled transder- mal fentanyl in the future.28 Fentanyl can be delivered across the mucous mem- branes of the mouth. Oral transmucosal fentanyl citrate (OTFC, Actiq Abbott Laboratories, Abbott Park, IL) has been used for breakthrough chronic cancer pain as well as acute postoperative pain.29,30 It would be a good choice if the intravenous route was temporarily unavailable for acute postoperative analgesia. Fentanyl, sufentanil, butor- phanol, heroin, oxycodone, and meperidine have been administered through the nasal mucosa, and morphine, codeine, fentanyl, heroin, and hydromorphone have been administered by inhalation.31 Ketamine Ketamine is a phencyclidine derivative occasionally employed as an anesthetic induction agent. Uniquely among induction agents, it produces what has been termed dissociative anesthesia. The analgesia does outlast the anesthetic effects and occurs at lower serum levels, so it can be useful in a decreased dosage as a postoperative anal- gesic. Ketamine may be given by intravenous, subcuta- neous, epidural (see below), oral, and transdermal routes.32 Ketamine produces analgesia by multiple mecha- nisms, including inhibition of N-methyl-D-aspartate (NMDA) receptors, depression of the thalamus while activating the limbic system, and direct spinal effects. NMDA receptors are involved in hyperalgesia or neuro- pathic pain, which suggests that ketamine would be a good choice for analgesia for these patients.33 A recent study in rats demonstrated that ketamine had different mechanisms of action depending on the presence or absence of inflammation. Antinociceptive effects were created by activation of the monoaminergic descending inhibitory system, whereas in a hyperalgesic state induced by inflammation, inhibition of NMDA activa- tion was the likely mechanism of the antihyperalgesia.34 Ketamine is a useful agent when narcotics and neurax- ial agents are contraindicated or working poorly. Chow and colleagues described a patient undergoing multiple thoracotomies whose pain management was complicated by infection and the development of neuropathic pain.35 Low-dose ketamine was used to decrease the need for narcotics after his fourth thoracotomy, with good results. It has also been suggested that ketamine should have pre- emptive effects because of its action at NMDA receptors. A landmark study in cholecystectomy patients found less postoperative pain, as measured by VAS scores and morphine consumption, in the group given low-dose intraoperative ketamine.36 An alternative explanation for the observed improved analgesia is that ketamine prevents the development of acute tolerance to opioids.37 Nonsteroidal Anti-inflammatory Drugs NSAIDs have proven to be a useful component of postop- erative pain relief. Many oral NSAIDs have been used including ibuprofen, naproxen, and ketoprofen. The only currently available parenteral NSAID is ketorolac tromethamine (Toradol, Roche Laboratories, Nutley, NJ). The addition of ketorolac to a patient-controlled epidural analgesia (PCEA) regimen employing hydromorphone alone significantly decreased the incidence of noninci- sional pain.38 Ketorolac is also employed in the treatment of breakthrough pain with otherwise satisfactory epidural analgesia. Ketorolac has several other features that make it useful in postoperative thoracotomy patients. These include its moderate potency (equivalent to morphine in some studies39 ); ease of administration by the intravenous and intramuscular routes; lack of acute tolerance, which may occur with even a single dose of opioid40 ; and lack of significant cardiorespiratory or central nervous system side effects. NSAIDs inhibit cyclooxygenase (COX), the enzyme that regulates the conversion of arachidonic acid to prostaglandins. There are two isoenzyme forms of COX. COX-1 is always present (constitutive). It modulates platelet activity and gastrointestinal cytoprotection and is involved in maintaining renal function in hypo- volemic states. COX-2 is thought to be inducible by inflammatory stimuli and is involved with inflamma- tion and pain. Conventional NSAIDs, such as indomethacin and ketorolac, which inhibit both COX-1 and COX-2, have been implicated in postoperative bleeding and gastric ulceration. They also may predis- pose to renal failure if the patient is concomitantly hypo- volemic or even just relatively dry, as post-thoracotomy patients often are. Specific inhibitors of COX-2 were developed in an attempt to prevent the side effects of conventional NSAIDs while maintaining the benefits. Current selective COX-2 inhibitors still exhibit some predilection for causing renal failure and gastric ulcera- tion but debatably to a lesser extent than conventional, 4 / Advanced Therapy in Thoracic Surgery
5. 5. nonselective NSAIDs.4143 The selective COX-2 inhibitors do not affect platelet function and have not been shown to increase postoperative blood loss. As a result they can be used perioperatively with relative impunity from hemorrhage. As of this writing, there is no parenteral COX-2 inhibitor available, although one is in US Food and Drug Administration trials. Regional Analgesia Techniques In the past two decades, regional analgesia techniques have become the primary means of providing optimal pain relief after a thoracotomy. Although the type C nerve fibers responsible for autonomically mediated visceral pain have abundant opioid receptors, type A delta nerve fibers, which mediate somatic incisional pain, contain a paucity of these receptors.44 Accordingly, systemically administered opioids have limited efficacy in controlling acute post-thoracotomy pain, especially that associated with activity. In contrast, local anesthetics, which are an integral component of most regional anal- gesia techniques, are very effective in blocking conduc- tion in both type A delta and C nerve fibers. The main blocks used for thoracotomy patients are intercostal nerve blocks, interpleural analgesia, thoracic paravertebral nerve blocks (TPVBs), and epidural analge- sia. Characteristics of these blocks are summarized in Table 1-5. Each may be performed as a single injection through a needle, but owing to the prolonged period of substantial pain experienced after a thoracotomy, catheter techniques are used more commonly (with the possible exception of intercostal nerve blocks, as discussed below). A standard 18- or 20-gauge epidural catheter may be placed through a hollow needle into the appropriate area for each block, and analgesic medication is administered through this catheter either as intermittent boluses or a continuous infusion. The former has the disadvantage of supplying fluctuating levels of analgesic in the area of the block and thus providing varying degrees of pain relief for the patient. The latter has the disadvantages of providing more analgesic than is necessary during periods of less painful stimulation, and promoting the accumulation of analgesic medication over time,45 unless appropriate decrements in infusion rates are made. With the goal of minimizing the disadvantages of both methods, low continuous (basal) infusion rates have been combined with intermittent boluses administered on an as-needed basis (which is usually patient controlled). Regional analgesia use in thoracotomies has several unique features compared with use in other types of surgery. First, all techniques except epidurals may be performed under direct vision from an internal approach before the chest is closed. This not only increases the ease with which the blocks are performed, but may also improve their success rate when compared with blocks performed via percutaneous techniques (although no studies have directly addressed this issue). As well, the risk of developing a pneumothorax, which is a potentially limiting factor for intercostal nerve blocks and interpleural analgesia, is irrele- vant because the thoracic cavity is open intraoperatively and chest tubes are used postoperatively. Finally, hypov- olemia is a relatively common occurrence in patients after thoracotomy because extensive fluid administration has been implicated in the development of postoperative pulmonary edema, especially after pneumonectomy.46 Therefore, regional analgesia techniques producing exten- sive blockade of the sympathetic nervous system and peripheral vasodilation may be accompanied by a signifi- cant risk of hypotension, and are often avoided. Postoperative Analgesia for Thoracotomy Patients: A Current Review / 5 TABLE 1-5. Summary of Factors Related to Regional Analgesia Techniques* Technique Ease of Analgesic Preservation Modification Hypotension Motor Blockade Urinary Retention Respiratory Insertion Efficacy of Pulmonary of Stress Depression Function Response Intercostal nerve blocks +++ + + Interpleural analgesia ++++ Thoracic paravertebral block ++ + ++ + Epidural analgesia ++ + + ++ = not a factor; = sometimes a factor; + to ++++ = degrees of being somewhat a factor to being an important factor. *For post-thoracotomy pain. With opioid/low-dose local anesthetic infusions.
6. 6. Of the four types of regional analgesia discussed in this chapter, epidural analgesia is the only technique for which agents other than local anesthetics have been successfully used. This is not surprising because the intercostal nerve block, interpleural analgesia, and paravertebral nerve block techniques depend primarily on blocking impulse transmission within somatic nerves. By contrast, blockade of pain pathways within the spinal cord may be accomplished by other drugs, most commonly opioids, delivered into the epidural space. Although several local anesthetic agents are available, bupivacaine has been the most popular choice for post- thoracotomy blocks over the past couple of decades, primarily because of its prolonged duration of action. Concentrations of 0.25 to 0.5% are necessary to provide adequate sensory blockade with most of the blocks discussed below, although lower concentrations have been used in the epidural space, when combined with opioids. Since its release in 1996, ropivacaine has been used increasingly for a variety of intraoperative and postopera- tive situations, and although the current literature regard- ing post-thoracotomy regional analgesia focuses on bupivacaine, ropivacaine will probably play a major role in clinical practice and the literature in the future. It is an amide local anesthetic structurally similar to bupivacaine that has the unique quality of being supplied as the pure S-()-enantiomer. This contrasts with the other local anesthetics, which exist as racemic mixtures of both the R-(+)- and S-()-enantiomers. Consequently, ropiva- caine produces less cardiovascular and central nervous system toxicity,47,48 similar analgesia, and a less intense and shorter duration of motor blockade than does bupiva- caine when administered into the epidural space.49,50 Low concentrations of epinephrine (1:100,0001:400,000) are frequently added to the solu- tion used for the regional analgesia techniques to decrease the quantity of medication absorbed into the systemic circulation. This should extend the duration and possibly improve the degree of analgesia, and decrease the risk of systemic toxicity from the drug. Lower peak plasma concentrations have been convincingly demonstrated when epinephrine has been added to the solutions used in intercostal nerve blocks,51 interpleural analgesia,52 and epidural analgesia,53,54 but data regarding the duration and quality of analgesia and systemic toxicity are more vari- able. There is even evidence that the addition of epineph- rine to epidural opioid solutions may increase the incidence of some opioid-related side effects, especially pruritus.5557 Epinephrine may also directly contribute to the pain relief achieved with epidural analgesic techniques by stimulation of 2-adrenergic receptors in the dorsal horn of the spinal cord.58 Ultralong-acting local anesthetics and opioids cur- rently under development have been advocated as a means of providing prolonged analgesia from a single dose. However, their eventual role in the management of acute post-thoracotomy pain is unclear because prolon- gation of analgesic effects is accompanied by a prolonga- tion of the duration of adverse events, which has particular relevance in the case of life-threatening cardio- vascular and respiratory depression. Despite their apparent usefulness in post-thoracotomy patients, regional analgesia techniques are not appropriate for all individuals. Absolute contraindications for all types of regional analgesia include patient refusal, an allergy to the medication to be used, a lack of resuscitative equip- ment, a lack of ability to use the resuscitative equipment, and an infection or tumor at the site of injection. Relative contraindications are often specific for the type of block and are discussed below for the individual techniques. Knowledge of the contraindications may be critical in choosing the specific block for a particular patient. Intercostal Nerve Block definition and technique Intercostal nerve block is a technique in which a local anesthetic is injected into the immediate vicinity of the intercostal nerve as it lies in the costal groove on the internal surface of the rib. In this position, the intercostal nerve traverses between the internal intercostal and inter- costalis intimus muscles and is located just caudad to the intercostal artery and vein. Local anesthetic is injected 7 to 8 cm from the posterior midline, proximal to the origin of the lateral cutaneous branch in the midaxillary line.59 Because there is a considerable overlap of sensory innervation of the thoracic dermatomes, it is necessary to block at least one level above and below the desired dermatomal level. Intercostal nerve blocks are often performed by a single-shot injection through a needle. There is limited spread of local anesthetic from one intercostal space to the next; therefore, separate injections at each level are usually necessary. For posterolateral thoracotomy inci- sions, intercostal nerve blocks are usually performed at T3 to T7. Three to 5 mL of local anesthetic is adminis- tered with each block; thus, a total of 20 to 25 mL of local anesthetic is used. Analgesia persists for 5 to 12 hours after a single injection,6063 and intercostal nerve blocks may be repeated as necessary. A variety of catheter tech- niques have also been described,62,64,65 although most of these studies involved the use of more than one catheter, which creates a cumbersome situation. 6 / Advanced Therapy in Thoracic Surgery
7. 7. mechanism of action Intercostal nerve blocks produce analgesia by direct blockade of the intercostal nerves. There is usually mini- mal or no spread of anesthetic proximally to the dorsal rami of the intercostal nerves or the sympathetic chain. efficacy Intercostal nerve blocks are moderately effective for post-thoracotomy pain. For example, Kolvenbach and colleagues detected adequate analgesia in approxi- mately 76% of their group of patients, as measured by the lack of need for supplemental opioids.62 When compared with placebo or parenteral opioids, intercostal nerve blocks have usually been shown to produce better pain control with lower pain scores and/or fewer supple- mental opioids.6468 Only two studies have compared intercostal nerve blocks with other regional techniques for post-thoracotomy pain. Asantila and colleagues compared intercostal nerve blocks with epidural analgesia with either bupivacaine or morphine, and found no significant differences between treatments with respect to pain scores or supplemental parenteral opioid requirements.69 More recently, Perttunen and colleagues randomized 45 patients to receive intercostal nerve blocks (performed at T3T7 via an internal approach and administered as a single injection just prior to wound closure), TPVBs, or continuous epidural analgesia with bupivacaine.70 In the first 4 hours after surgery, pain scores during coughing were significantly lower in the intercostal nerve block group than in the other two groups. No differ- ences were noted in supplemental morphine consumption, pain scores at rest, or pain scores with coughing after the initial 4-hour period. However, the authors emphasize that pain relief in all patients was only fair (VAS pain scores of 2862/100 at rest and 6291/100 with coughing), and opti- mizing the management of these techniques may have produced different results. Analgesic efficacy may be limited in intercostal nerve blocks owing to a lack of blockade of the dorsal rami, which can result in persistent pain at the medial edge of the incision, and muscles and ligaments in the surround- ing area. Failure to block the sympathetic chain, vagus, and phrenic nerves may further limit the ability of inter- costal nerve blocks to provide optimal pain relief after thoracotomy. Intercostal nerve blocks also appear to be moderately effective in improving pulmonary function. This is suggested in several,64,66,71,72 but not all,65 studies by higher values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and/or peak expiratory flow rate (PEFR) in patients receiving these blocks compared with values in patients receiving a placebo or parenteral opioids. Compiling the results of several studies, Richardson and colleagues demonstrated an overall 55% preservation of spirometric function (vs preoperative values) with intercostal nerve blocks by 48 hours post- thoracotomy.8 Despite the above observations, most stud- ies have failed to demonstrate that intercostal nerve blocks decrease the incidence of postoperative complica- tions in post-thoracotomy patients. Furthermore, although Deneuville and colleagues showed that inter- costal nerve blocks were associated with fewer postopera- tive respiratory complications than was as-needed parenteral opioid, the incidence of complications with intercostal nerve blocks was identical to that with fixed- schedule intramuscular opioid injections.65 advantages and disadvantages The main advantage of intercostal nerve blocks is the ease with which they can be performed.61 They require little training and no special equipment. The technique is quite safe, and any significant complication usually occurs within 30 minutes of performing the block. As such, no special monitoring is necessary for patients with these blocks beyond the immediate post-block time period. The main disadvantages of intercostal nerve blocks are the necessity of performing separate blocks at multiple levels, and the relatively short duration of analgesia achieved via the single-injection techniques. adverse effects The most common adverse effect associated with the use of intercostal nerve blocks for thoracotomy is the devel- opment of high systemic blood levels of local anesthetic. This is a consequence of both the volume needed for injections at multiple levels and the vascularity of the area of injection. Peak blood levels of local anesthetic occur at 5 to 20 minutes,61,64,73 and they are higher than with interpleural analgesia, TPVBs, and epidural analge- sia.70,74 Case reports of spinal anesthesia associated with the use of intercostal nerve blocks have also been reported.75,76 This has been postulated to be due to retro- grade intraneural spread of local anesthetic to the subarachnoid space. Most cases have involved intercostal nerve blocks performed by an internal approach during thoracotomy, possibly because of the more medial injec- tion of the local anesthetic in these circumstances. contraindications There are no absolute contraindications specific to inter- costal nerve blocks. The main relative contraindication of intercostal nerve blocks when used for post-thoracotomy analgesia is in patients for whom the effects of high Postoperative Analgesia for Thoracotomy Patients: A Current Review / 7
8. 8. systemic blood levels of local anesthetic may be particu- larly detrimental, which includes patients with cardiac conduction defects and seizure disorders. Interpleural Analgesia definition and technique The term interpleural analgesia refers to a technique whereby local anesthetic is placed into the interpleural space, located between the visceral and parietal pleurae. The term intrapleural analgesia is often used interchange- ably with interpleural analgesia, but the former is anatomically incorrect. For thoracotomy patients, a multiorifice epidural catheter is usually inserted into the interpleural space under direct vision by the surgeon prior to chest closure, and a local anesthetic is adminis- tered either as a continuous infusion or intermittent bolus doses. Some authors emphasize suturing the inter- nal tip of the catheter high in the interpleural space (in the cranial portion of the thoracic cage) to prevent dislodgment,77 whereas others recommend placing the tip at the level of the incision.78 Table 1-6 presents examples of dosage regimens. None has been demonstrated to be superior to the others. mechanism of action Interpleural analgesia produces pain relief primarily by diffusion or bulk flow of local anesthetic through the parietal pleura, into the subpleural space, and finally to the intercostal nerves. The resultant effect is a multilevel intercostal nerve block.79 Interpleural analgesia tech- niques may also block other nervous structures including the vagus and phrenic nerves as they traverse through the interpleural space,77 pain receptors in the parietal pleura, and the thoracic sympathetic chain, by diffusion of local anesthetic into the paravertebral space. The clinical importance of blockade at these secondary sites is unclear and may contribute to the variable results in studies examining the efficacy of interpleural analgesia. efficacy The efficacy of interpleural analgesia for post-thoracotomy pain is controversial.80 Compared with placebo or parenteral opioids, interpleural analgesia has been shown to improve analgesia in some studies,81,82 and to have minimal or no effect in others.8385 Interpleural analgesia has also been demonstrated to produce a degree of anal- gesia similar to TPVB and thoracic epidural analgesia with bupivacaine in some studies,78,86 but less than thoracic epidural bupivacaine, lumbar epidural hydro- morphone, and lumbar epidural morphine in others.74,87,88 The lack of consistent efficacy for post-thoracotomy pain has been primarily attributed to the loss of local anesthetic by drainage through chest tubes. Ferrante and colleagues documented a 30 to 40% loss of an injected dose of bupivacaine over a 4-hour period through the chest tubes.89 For interpleural analgesia administered via the bolus method, clamping the chest tubes for 15 to 30 minutes after each dose has been advocated to help circumvent this problem,77 although the safety and effi- cacy of such a maneuver has been questioned.8 Other factors that may contribute to the lack of anal- gesic efficacy are dilution of local anesthetic with pleural exudate, and uneven distribution of local anesthetic throughout the pleural space. The latter may occur because of inflammation of the pleura by the current surgical procedure and/or the presence of fibrous tissue from previous pleural disease or thoracotomy. As well, the distribution of local anesthetic within the inter- pleural space is gravity dependent.90 The upright position assumed by post-thoracotomy patients, because of its beneficial effects on pulmonary function, encourages pooling of the local anesthetic in the inferior thoracic cage, thereby contributing to lesser analgesia at the more cranial thoracic dermatomes. Finally, the dorsal rami of the thoracic spinal nerves are not blocked by interpleural techniques; thus, patients may experience pain in the medial part of the incision and paravertebral surround- ing muscles and ligaments.64 The effects of interpleural analgesia on postoperative pulmonary function are likewise unimpressive. Most studies have failed to demonstrate an improvement in FEV1, FVC, PEFR, arterial blood gas values, and/or pulmonary complications compared with these effects when placebo or parenteral opioids are used.74,83,84 In Richardson and colleagues review of spirometric function with different analgesic techniques post-thoracotomy, 8 / Advanced Therapy in Thoracic Surgery TABLE 1-6. Examples of Dosing Regimens for Interpleural Analgesia Study Intraoperative Regimen Postoperative Regimen Tartiere et al, 10 mL 0.25% bupivacaine 199181 q8h Richardson et al, 20 mL 0.25% bupivacaine at 0.5% bupivacaine 199578 chest closure 0.1 mL/kg/h infusion Stromskag et al, 20 mL 0.375% 199090 bupivacaine prn Schneider et al, 30 mL 0.5% bupivacaine 199384 q4h Mann et al, 199282 20 mL 0.25% bupivacaine q4h Silomon et al, 20 mL 0.5% bupivacaine 200083 q4h Raffin et al, 199485 0.15 mL/kg 2% lidocaine with 0.05 mL/kg/h 2% 1:200,000 epinephrine after lidocaine with chest closure 1:200,000 epinephrine infusion prn = according to circumstances.
9. 9. an overall 35% preservation of function (vs the preoper- ative values) was noted for interpleural analgesia by 48 hours postoperatively.8 This was lower than for all the other techniques examined, including intercostal nerve blocks, thoracic paravertebral, and epidural analgesia. In two randomized studies comparing interpleural analgesia and TPVB, analgesia for the two techniques was equiva- lent, but patients receiving interpleural analgesia demon- strated significantly worse FVC and FEV1 values.78,91 This observation led to the suggestion that interpleural anal- gesia may cause direct impairment of diaphragmatic and intercostal muscle function, either by diffusion of local anesthetic into the diaphragm and/or intercostal muscles, with direct inhibition of their contractile function,91 or by blockade of the phrenic nerve as it travels through the mediastinum and/or at its terminal branches innervating the diaphragm. No studies to date have confirmed the validity of either theory.92 advantages and disadvantages The primary advantage of interpleural analgesia for post- thoracotomy pain is the ease with which the technique can be performed. It is also relatively safe, and no special monitoring is necessary for patients receiving this form of analgesia.77 The main disadvantage of interpleural analgesia is the lack of consistent beneficial effects on pain relief and pulmonary function in the post-thoracotomy patient. Possible explanations for this have been discussed above. adverse effects The main adverse effects of interpleural analgesia for post- thoracotomy analgesia include toxicity owing to excessive systemic absorption of local anesthetic, blockade of the thoracic sympathetic chain, and stellate ganglion blockade (with an ipsilateral Horner syndrome).93 Systemic local anesthetic toxicity is rare because plasma concentrations usually remain below levels associated with significant toxicity.81,94,95 When administered as a bolus dose, peak blood levels occur 5 to 30 minutes after injection. Similarly, blockade of the thoracic sympathetic chain rarely produces clinically significant hypotension and bradycardia. This lack of hemodynamic effects has tradi- tionally been attributed to the unilateral nature of the sympathetic block, although Ramajoli and De Amici have convincingly demonstrated bilateral sympathetic blockade of the thorax and abdomen with unilateral interpleural instillation of both 0.25 and 0.5% bupivacaine.96 Thus, hemodynamic stability is probably due to incomplete blockade of the upper thoracic ganglion, resulting in little or no effect on the cardiac sympathetic fibers and allowing compensatory vasoconstriction of the upper extremities. contraindications There are no absolute contraindications specifically related to the technique of interpleural analgesia. Relative contraindications include conditions in which there is an anticipated lack of efficacy, such as with pleural fibrosis, previous surgical or chemical pleurodesis, and bron- chopleural fistula or empyema; and patients for whom the effects of high systemic blood levels of local anes- thetic may be particularly detrimental (as discussed above under Intercostal Nerve Block). Thoracic Paravertebral Nerve Block definition and technique After its first performance in 1905 by Hugo Sellheim, TPVB enjoyed an initial period of popularity, followed by a dramatic decline in use in the middle of the twentieth century.97 In the past two decades, however, there has been a resurgence of interest in the technique, particu- larly in Europe. TPVB is a technique whereby local anesthetic is injected into the paravertebral space in the thoracic region. It has also been referred to as extrapleural, extrapleural paravertebral, and extrapleural intercostal analgesia. As depicted in Figure 1-2, the paravertebral space is a wedge-shaped region adjacent to the thoracic vertebrae in the vicinity where the spinal nerves emerge from the intervertebral foramina. Its boundaries are as follows: posteriorly, the superior costotransverse liga- ment; laterally, the posterior intercostal membrane; ante- riorly, the parietal pleura; and medially, the posterolateral aspect of the vertebrae, intervertebral disk, and interver- tebral foramen. The origin of the psoas muscle forms the inferior boundary of the paravertebral space; thus, spread of local anesthetic below T12 is uncommon. The cranial boundary of the paravertebral space has not been Postoperative Analgesia for Thoracotomy Patients: A Current Review / 9 Subserous fascia Sympathetic chain Interpleural space Extrapleural compartment Subendothoracic compartment Intercostal nerve Posterior primary rami Superior costotransverse ligament Right lung Left lung Azygos vein Esophagus Thoracic duct Descending aorta Pleura Visceral ParietalEndothoracic fascia FIGURE 1-2. Anatomy of the thoracic paravertebral space. Reproduced with permission from Karmaker MK.98
10. 10. defined, and radiocontrast dye has been observed in the cervical region after thoracic paravertebral injection.98 The thoracic paravertebral space is in continuity with the epidural space medially via the intervertebral foramen, the intercostal space laterally, and the contralateral paravertebral space via the prevertebral and epidural spaces.98 The paravertebral space is traversed by the inter- costal nerves, their dorsal rami, the rami communicantes, and the sympathetic chain. As with other techniques, TPVB may be performed by direct injection through a needle or an indwelling catheter, both of which may be introduced either percuta- neously or under direct vision before the chest is closed. Sabanathan and colleagues have described a technique for use during thoracotomy that involves reflecting the pari- etal pleura from the posterior wound margin onto the vertebral bodies to form an extrapleural pocket.99 A percu- taneously placed catheter is then placed into this pocket and positioned under direct vision so that it lies against the angles of the exposed ribs. Richardson and Lonnqvist have employed combined techniques whereby a percuta- neously placed catheter is inserted before the surgery begins and a bolus dose of local anesthetic is administered to provide intraoperative anesthesia.97 Before chest closure, methylene blue is injected through the catheter, and if the spread of dye is not optimal, the catheter is reinserted by the surgeon. Video-assisted placement of a paravertebral catheter during thoracoscopy has also been reported.100 Table 1-7 presents various dosage regimens for TPVB. Continuous infusion of local anesthetic through a paravertebral catheter provides better pain control than do intermittent bolus injections.101 mechanism of action TPVB produces analgesia by blockade not only of the intercostal nerves but also of their dorsal rami and the sympathetic chain. Owing to the continuous nature of the paravertebral space, local anesthetic applied at one level spreads to multiple contiguous dermatomes. Using 15 mL 0.5% bupivacaine, Cheema and colleagues demonstrated a somatic sensory block extending for a mean of 5 (range 1 to 9) dermatomes, and a sympathetic block over an average of 8 (range 6 to 10) dermatomes.102 However, the extent of spread is variable, as is evidenced by these large ranges; thus, it may be necessary to perform injections at more than one site to reliably anes- thetize more than three to four segments. A small amount of local anesthetic may also exit the interverte- bral foramina to enter the epidural space, but whether this contributes significantly to the analgesic effects of TPVB is questionable.98 efficacy The efficacy of TPVB for post-thoracotomy pain control has been well established. Lower pain score and opioid- sparing effects have been noted in several studies compar- ing TPVB with placebo and parenteral opioids,103106 although supplemental opioids were often still necessary. In comparison to epidural blockade with local anesthetics and/or opioids, TPVB has frequently demonstrated simi- lar or better pain relief, accompanied by less nausea, vomiting, hypotension, and urinary retention.107110 Most studies have demonstrated a significant improve- ment of post-thoracotomy pulmonary dysfunction with TPVB compared with placebo or parenteral opioids, as demonstrated by higher FEV1, FVC, and/or PEFR values.104,105,106,111 In Richardson and colleagues review of various techniques for post-thoracotomy analgesia, TPVB demonstrated the best preservation of pulmonary func- tion.8 FEV1, FVC, and/or PEFR values had all returned to approximately 75% of their preoperative value by 48 hours postoperatively in patients who had received TPVB. When TPVB has been compared directly with thoracic epidural analgesia, most studies have demonstrated similar effects on pulmonary function for the two techniques,109,110 although TPVB was associated with higher values of PEFR and oxygen saturation as measured by pulse oximetry (SpO2) in one study by Richardson and colleagues group.107 As noted previously (see Interpleural Analgesia), TPVB has been demonstrated to produce both better and similar effects on pulmonary function tests when directly compared with interpleural analgesia.70,112 Likewise, there is a limited quantity of evidence that 10 / Advanced Therapy in Thoracic Surgery TABLE 1-7. Examples of Dosage Regimens for Thoracic Paravertebral Blockade Study Intraoperative Regimen Postoperative Regimen Carabine et al, 1995103 5 mL 0.25% bupivacaine after chest closure 0.25% bupivacaine 5 mL/h infusion Catala et al, 1996101 20 mL 0.375% bupivacaine q6h or 15 mL 0.375% bupivacaine loading dose, then 5 mL/h 0.375% bupivacaine infusion Barron et al, 1999105 0.3 mL/kg 1% lidocaine before chest closure or 0.1 mL/kg/h 1% lidocaine infusion or 0.1 mL/kg/h 0.3 mL/kg 0.25% bupivacaine before chest closure 0.25% bupivacaine infusion Berrisford et al, 1990111 20 mL 0.5% bupivacaine after chest closure Approximately 0.1 mL/kg/h 0.5% bupivacaine Mathews and Govenden, 1989108 10 mL 0.25% bupivacaine after chest closure 310 mL/h 0.25% bupivacaine Richardson et al, 1999107 20 mL 0.25% bupivacaine during chest closure 0.1 mL/kg/h 0.5% bupivacaine infusion
11. 11. TPVB may decrease the risk of pulmonary complications compared with placebo and parenteral opioids. Sabanathan, Berrisford, and colleagues, in two separate studies (with possibly overlapping subjects), have reported fewer pulmonary complications in patients receiving TPVB compared with placebo.104,111 TPVB has also been shown to suppress the stress response, as measured by serum cortisol and glucose levels, and in this respect it functioned better than thoracic epidural analgesia.107 advantages and disadvantages TPVB has been described as being quick and easy to perform.98,112,113 This statement should be interpreted cautiously, however, as it was made by the main authors regarding TPVB in the literature today, and their experi- ences may not be applicable to other institutions. This caution may be especially relevant for centers in North America, where TPVB is rarely taught in the anesthesiol- ogy and surgery training programs. Other advantages of TPVB include the lack of urinary retention and motor blockade of the lower extremities owing to the thoracic and unilateral location of the block.102,114 As well, the unilateral nature of the block results in little/no direct effects on hemodynamics,102 and the doses of local anesthetic are usually less than those associated with systemic toxicity.70 Even when higher levels have occurred, there has been no evidence of systemic toxicity.45,110 Accordingly, no special monitoring is necessary for patients with these blocks beyond the usual postoperative care.112 As TPVB is dependent on the use of local anesthetics for postoperative use, opioid- related risks are theoretically avoided. However, supple- mentation with systemic opioids is often used; thus, opioid adverse effects may be minimized but not absent. The main disadvantage of this technique is that it is more difficult to perform than the intercostal nerve and interpleural blocks. As well, patients with a previous thoracotomy are usually inappropriate candidates for the block since the paravertebral space may be obliterated by scar tissue. The technique may likewise be unsuitable for patients undergoing a pleurectomy, although successful use of TPVB has been reported, provided the parietal pleura covering the vertebral bodies and a few centime- ters distally is left intact.106 adverse effects The incidence of adverse effects with TPVB in the post- thoracotomy population is 10% or lower.112,115 The most frequent adverse event is hypotension,115 which has been primarily attributed to the unmasking of relative hypo- volemia as hypotension does not occur in well-hydrated patients receiving TPVB for the treatment of chronic pain syndromes.98,102,112 Other complications, which occur much less frequently, are inadvertent puncture of the epidural or subarachnoid space owing to a faulty tech- nique,97 and unilateral Horner syndrome because of the cephalad spread of anesthetic to the cervical sympathetic structures. No fatality directly related to TPVB has been reported in the literature.98,112 contraindications As alluded to above, a previous ipsilateral thoracotomy would be a relative contraindication to the technique because of a possible obliteration of the paravertebral space. An empyema is not directly affected by manipula- tions in the paravertebral space, but the accompanying acidosis and hyperemia may limit the efficacy of the TPVB and increase the risk of systemic absorption of local anesthetic. Anticoagulation is a relative contraindi- cation to the technique, but the paravertebral space is less vascular than the epidural space; thus, the risk of venous puncture is less than with epidural analgesia. As well, the consequences of a unilateral paravertebral space hema- toma are small compared with the potentially cata- strophic consequences of an epidural hematoma.112 Similarly, TPVB is relatively contraindicated in patients with raised intracranial pressure because of the possibil- ity of inadvertent dural puncture and subsequent brain- stem herniation. However, the risk of puncture is less than with epidural analgesia, so in this situation, TPVB would be the best choice of the two techniques. Epidural Analgesia definition and technique Epidural analgesia refers to the technique of injecting analgesic medication into the epidural space, surround- ing the spinal cord. As with most of the other regional techniques discussed heretofore, epidural analgesia is almost exclusively administered via an indwelling catheter when used for post-thoracotomy pain relief. Similar effects may be achieved by injecting analgesic medication into the subarachnoid space (albeit with lower doses),116 but the technique is rarely used in the United States because of concerns with introducing a catheter into this space. The intimate proximity of the subarachnoid space to the spinal cord poses a risk of injury to the spinal cord, and an association between the development of cauda equina syndrome and subarach- noid microcatheters (also known as spinal micro- catheters) has been suggested.117 Local anesthetics and opioids are the two main classes of drugs used for epidural analgesia in post-thoracotomy patients. Other drugs that have been used in the epidural space, either alone or as adjuncts, are discussed later (see Postoperative Analgesia for Thoracotomy Patients: A Current Review / 11
12. 12. Other Agents). In the early 1980s, epidural morphine was popular, primarily because of its hemodynamic stability compared with epidural local anesthetics and its relatively long duration of action.5 The latter permitted bolus dosing on an as-needed basis every 6 to 24 hours. The risk of respiratory depression and slow onset of action with epidural morphine promoted the search for alternative opioids,118 thus leading to the use of more lipophilic epidural opioids such as fentanyl and its analog, sufentanil. Owing to the short duration of action of these opioids, continuous infusions are necessary. Most recently the synergistic effects of combining local anesthetics and opioids in the epidural space have been recognized.119 This synergism has been attributed to the facilitation of opioid transport from the epidural space to the subarachnoid space by local anesthetic,120 and production of a conformational change in the spinal opioid receptor by local anesthetic agents, such that opioid binding is facilitated.121 Accordingly, continuous infusions of opioidlocal anesthetic combinations have become popular, with the goal of providing similar or improved analgesia with lower doses of both agents, so that the incidence of adverse effects is reduced. Although similar or improved analgesia has been achieved in several studies,122126 a reduction in adverse effects has not been universally accomplished (see Effects Related to Injection of Epidural Local AnestheticOpioid Combinations, below). Current literature suggests that the combination of 10 to 12.5 g/mL fentanyl (or 1 g/mL sufentanil) and 0.1 to 0.125% bupivacaine is closest to the ideal for post-thoracotomy patients, producing a maximum of pain relief and minimum of side effects.6,127 Of interest, the addition of bupivacaine does not seem to improve analgesia when added to epidural meperidine.128 This may be because meperidine has significant local anesthetic properties itself and has even been used as the sole anesthetic for lower abdomi- nal surgery when administered in the subarachnoid space.129 Table 1-8 presents several examples of epidural analgesia regimens. There is controversy as to whether epidural catheters should be inserted into the thoracic or lumbar region for thoracotomy patients. Owing to the proximity of the spinal cord to the epidural space in the thoracic region and the greater technical difficulty of entering the epidural space at this level of the spinal column, many anesthesiologists are hesitant to insert a thoracic epidural catheter. They are supported by evidence that equivalent analgesia may be achieved by lumbar and thoracic epidural injections in post-thoracotomy patients.120,130134 In contrast, advocates of thoracic epidural catheters emphasize that higher volumes and/or higher doses of epidural opioids and/or local anesthetics were needed with the lumbar route to produce equivalent analgesia in many of these studies, thereby suggesting that the lumbar route may be acceptable but not optimal. As well, there is no evidence that complication rates are higher with thoracic than with lumbar epidural catheters,135 and many of the potential advantages of epidural analgesia discussed below rely on blockade of the cardiac sympa- thetic fibers at T1 to T5, which is more easily accom- plished with a thoracic than with a lumbar epidural catheter. With these considerations in mind, the approach at our institution is to preferentially place a thoracic epidural catheter; however, a high lumbar catheter is used if this is unsuccessful. mechanism of action The mechanism of action of epidural opioids and local anesthetics differs. Local anesthetics applied to the epidural space act primarily by blockade of nerve impulse conduction in the axonal membrane of the spinal nerve roots as they traverse the epidural space.136 Diffusion of local anesthetic into the long tracts of the spinal cord may further contribute to the analgesia produced by epidural local anesthetics. The various types of nerve fibers exhibit differential sensitivity to local anesthetics: sympathetic fibers are the most easily blocked, and motor fibers are the most resistant.137 Consequently, the concentration of local anesthetic is the primary determinant of the depth of blockade, with higher concentrations producing more motor blockade. The actual extent of blockade along the spinal canal 12 / Advanced Therapy in Thoracic Surgery TABLE 1-8. Examples of Dosing Regimens for Epidural Analgesia Solution Infusion Rate Bolus Doses Fentanyl 10 g/mL 0.51 g/kg/h 1015 g q1015 min prn Sufentanil 1 g/mL 0.10.2 g/kg/h 57 g q1015 min prn Morphine 36 mg q612h prn Morphine 0.01% 0.50.8 mg/h 0.20.3 mg q1015 min prn Hydromorphone 0.81.5 mg q46h prn Hydromorphone 0.005% 0.150.3 mg/h 0.150.3 mg q1015 min prn Fentanyl 10 g/mL + 68 mL/h 12 mL q1015 min prn bupivacaine 0.750.125% Sufentanil 1 g/mL + 68 mL/h 12 mL q1015 min prn bupivacaine 0.750.125% Morphine 0.01% + 68 mL/h 12 mL q1015 min prn bupivacaine 0.750.125% Hydromorphone 0.0025% 68 mL/h 13 mL q1015 min prn 0.005%+ bupivacaine 0.750.125% Data from University of Texas M. D. Anderson Cancer Center protocol and DeLeon-Casasola OA and Lema M.154 prn = according to circumstances.
13. 13. depends primarily on the volume administered, and because of the greater sensitivity of the sympathetic fibers, the extent of sympathetic blockade may be greater than the somatic sensory block. Epidural opioids exert their primary therapeutic effects by binding to specific opioid receptors in the substantia gelatinosa of the dorsal horn of the spinal cord gray mater.136,138 This region contains interneurons involved in the ascending pain pathways (the spinothala- mic and spinoreticular tracts). Opioid receptors are located both presynaptically and postsynaptically, and they function to inhibit the release of neurotransmitters from primary sensory neurons and block the depolariza- tion of post-synaptic neurons, respectively.44 The term selective spinal analgesia has been used to denote analge- sia attributable to these spinal cord opioid receptors. Before reaching the spinal cord, opioids injected into the epidural space must first travel through the dura mater, subdural space, arachnoid mater, subarachnoid space (containing the cerebrospinal fluid), and pia mater. The epidural space contains an abundance of fat tissue and an extensive venous plexus, and 90 to 97% of an injected dose is absorbed into these compartments,139141 thereby never reaching the subarachnoid space. Epidural opioids may also produce analgesia at a supraspinal level (termed supraspinal analgesia) by bind- ing to opioid receptors in the brain. Opioids gain access to these sites via two main pathways: absorption into the epidural veins and subsequent entry into the systemic circulation, and rostral travel through the cerebrospinal fluid to the brain. After a bolus injection of all epidural opioids, plasma levels peak at approximately the same time as with an intramuscular injection,139,142,143 and in some studies have achieved values high enough to contribute to analgesia.139,142,144146 Plasma opioid levels fall quickly, however, and are of little importance beyond the first hour after epidural bolus administration for all agents.139,142,146 A different scenario arises when lipophilic agents (such as fentanyl and sufentanil) are administered by continuous epidural infusion or repeat bolus. Continuing systemic absorption of these agents results in accumulation, and some studies have recorded systemic plasma levels within the usual therapeutic range for these drugs, when administered by these meth- ods.123,143 Similarly, Miguel and colleagues and Sandler and colleagues have demonstrated that epidural infu- sions of fentanyl and sufentanil produce plasma levels similar to those with intravenous infusion, when titrated to equivalent analgesia.1 4 7 , 1 4 8 This suggests that supraspinal analgesia may be a major contributor to the overall analgesic effect when lipophilic opioids are administered in this manner. Rostral travel through the cerebrospinal fluid of opioids injected into the epidural space is most promi- nent with morphine, as its relative hydrophilic properties limit its diffusion out of the subarachnoid space, thereby allowing greater quantities of morphine to be retained in the cerebrospinal fluid for a prolonged period of time.149 Morphine travels cranially via the slow process of cere- brospinal fluid bulk flow, leading to peak levels of morphine in the cervical cord region by 3 to 5 hours after lumbar epidural injection.136,150 Movement through the cerebrospinal fluid for more lipophilic opioids may also occur, especially with large bolus doses, but the quantities of drug detected in the cervical cord and/or cisterna magna have been small, and their contribution to the analgesia achieved with these agents is unknown.146,151 efficacy The efficacy of epidural analgesia in providing pain relief after thoracotomy depends on the drug(s) used. Epidural analgesia with local anesthetics alone is more effective in providing analgesia than are parenteral opioids, but the concentrations needed to accomplish this (eg, 0.5% bupivacaine) are accompanied by a signif- icant risk of hypotension. When lower concentrations have been used, supplemental parenteral opioids are usually necessary.70,107,152 The efficacy of epidural morphine in providing post-thoracotomy analgesia is undisputed. It is consid- ered the gold standard for epidural opioid analgesia. Pain scores and/or the need for supplemental anal- gesics are universally lower for epidural morphine than for parenteral morphine, and these effects are accom- plished using lower doses of epidural morphine, which last longer than parenteral morphine.5 , 1 5 2 , 1 5 3 The lipophilic opioids are also effective in providing analge- sia after thoracotomy when administered via the epidural route. However, as discussed previously, there is evidence that continuous epidural infusions of these agents produce post-thoracotomy pain relief primarily by the systemic absorption of the opioid and may offer little advantage over the less complicated intravenous route of administration.154 The opioidlocal anesthetic combinations popular today are also very effective in providing pain relief after thoracotomy. As combinations are relatively new tech- niques and the efficacy of epidural analgesia for post- thoracotomy pain has already been established, there has been little interest in performing studies comparing the efficacy of combinations to that of parenteral opioids or placebos. Nevertheless, improved analgesia has been noted with both epidural morphinebupivacaine and epidural fentanylbupivacaine infusions compared with parental opioids.152,155 Postoperative Analgesia for Thoracotomy Patients: A Current Review / 13
14. 14. Studies comparing epidural analgesia with other modes of regional analgesia in post-thoracotomy patients are few, and their interpretation has been confounded by the use of a variety of different medications in the epidural space. Three studies have used epidural local anesthetics alone. Brockmeier and colleagues showed no difference in analgesic efficacy between 0.375% epidural bupivacaine and interpleural analgesia.86 Richardson and colleagues demonstrated better analgesia with TPVB than with epidural analgesia, but the TPVB group received 0.5% bupivacaine and the epidural group received only 0.25% bupivacaine.107 A final study compared 0.25% epidural bupivacaine with 0.25% TPVB bupivacaine and 0.5% interpleural bupivacaine.70 All techniques produced similar analgesia at rest, but the intercostal nerve blocks group had better dynamic pain relief for the first 4 hours after thoracotomy. In a study of epidural analgesia using a combination of fentanyl and bupivacaine, analgesia was superior to that produced by TPVB,114 although this effect did not persist beyond the first postoperative day. Evidence regarding the efficacy of epidural analgesia in improving pulmonary function and decreasing pulmonary morbidity in the post-thoracotomy patient is conflicting. Many studies have revealed no difference in arterial blood gas results, spirometry measurements, or pulmonary complications when epidural analgesia has been compared with parenteral opioids or other types of regional analgesia in this population.69,88,109,153,156160 In Richardson and colleagues review of different techniques for post-thoraco- tomy analgesia discussed previously, epidural analgesia with local anesthetics and/or opioids resulted in a moder- ate preservation of pulmonary function.8 By 48 hours after surgery, FEV1, FVC and/or PEFR values had returned to approximately 55% of their preoperative values in patients who had received epidural analgesia, which was similar to the results obtained with intercostal nerve blocks but worse than the 75% values observed with TPVB. For those studies that have shown an improvement in pulmonary parameters, most have demonstrated improvement in only some of the parameters measured. For example, Guinard and colleagues demonstrated higher FVC and FEV1 values for thoracic epidural fentanyl when compared with intravenous fentanyl, but no difference in arterial blood gas results or the number of patients with abnormalities on chest radiographs.132 Salomaki and colleagues have shown lower PaCO2 values with epidural fentanyl but similar PaO2 and incidences of atelectasis compared with intravenous fentanyl.161 Two articles from Hasenbos and colleagues are the only stud- ies that have found both improved arterial blood gases (PaCO2 less elevated above preoperative levels) and reduced incidence of pulmonary complications.162,163 However, these studies were not blinded, and the opioid examined was nicomorphine, the 3,6-dinicotinoyl ester of morphine, which is not available in North America. As well, the sole analgesic in the nonepidural groups was intramuscular nicomorphine, administered in as-needed doses by the nursing staff. By providing parenteral opioid in this manner, analgesic therapy in these groups may not have been optimized. A recent meta-analysis of the pulmonary effects of various analgesic regimens in a wide variety of surgical procedures (including but not restricted to thoraco- tomies) revealed only a diminished incidence of atelecta- sis with epidural opioids and a decreased incidence of pulmonary infection and overall pulmonary complica- tions, plus an increased PaO2 with epidural local anes- thetics.164 Of interest, the authors emphasize the lack of difference in spirometry results between the different methods of analgesia and suggest that there is no ratio- nale for using these surrogate measures of pulmonary outcomes. Epidural analgesia has little, if any, impact on modify- ing the stress response to surgery in the post-thoracotomy population.107,165 This has been attributed to incomplete blockade of the afferent sensory nervous input from the site of surgery and the release of components of the stress response, such as cytokines, directly into the bloodstream from the site of tissue injury.166 advantages and disadvantages One major advantage of epidural analgesia is related to the use of opioids in the epidural space. Systemic absorp- tion and/or cephalad spread of epidural opioid may alle- viate the shoulder pain commonly associated with thoracotomies, and even neck incisions for esophagec- tomies. In our institution, we do not routinely use supple- mental parenteral opioids for pain in these two locations. If necessary, NSAIDs and acetaminophen are almost always sufficient adjuvants to our epidural analgesia. Thoracic epidural analgesia with local anesthetics (alone or in combination with opioids) may have unique advan- tages in patients with coronary artery disease. Blockade of the cardiac sympathetic fibers innervating the heart (T1T5) results in small reductions in heart rate, systemic vascular resistance, and possibly cardiac output,167,168 thereby decreasing myocardial oxygen demand. At the same time, myocardial oxygen supply may improve, particularly in areas at most risk of ischemia. Thoracic epidural analgesia with local anesthetic has been demonstrated to produce dilatation of stenotic coronary arteries,169 redistribution of blood flow from the epicardium to endocardium,170 and redistribution of blood flow specifically toward ischemic regions of the myocardium.170 Maintaining the systemic blood pressure close to the normal range (eg, mean arterial 14 / Advanced Therapy in Thoracic Surgery
15. 15. pressure < 20% below baseline) is necessary for these effects to be most evident.171 Another potential benefit of epidural analgesia in the patient with coronary artery disease relates to coagulation. Local anesthetic may be absorbed from the epidural space in quantities sufficient to interfere with platelet aggrega- tion,172,173 thereby counteracting the hypercoagulable state associated with major surgery and potentially diminishing the risk of coronary artery thrombosis formation. Despite the above observations, there have been no properly conducted randomized controlled trials demon- strating decreased risk of myocardial ischemia/infarction through the use of epidural analgesia in any group of patients postoperatively, let alone those having thoraco- tomies. As well, there is concern that blockade of the sensory innervation of the upper thoracic region may simply obliterate the pain of myocardial ischemia, thus removing an important warning signal of impending myocardial infarction.174 Epidural analgesia may also decrease the risk of postop- erative arrhythmias. This is of particular relevance in the post-thoracotomy situation as supraventricular arrhyth- mias (especially atrial fibrillation) occur in approximately 15% of patients after lung surgery, and recurrent episodes have been associated with increased perioperative mortal- ity.175 Animal studies suggest that thoracic epidural analge- sia with local anesthetic may reduce the risk of ventricular tachyarrhythmias and reentry supraventricular arrhyth- mias,176178 an effect that has been attributed to cardiac sympathetic blockade. In humans a retrospective review by Groban and colleagues noted a significantly lower inci- dence of atrial arrhythmias while thoracic epidural analge- sia (with opioid or opioid plus local anesthetic) was in use compared with the incidence after the epidural was removed on the second or third postoperative day.179 In a prospective, randomized study comparing thoracic epidural bupivacaine with thoracic epidural morphine, Oka and colleagues demonstrated a lower incidence of supraventricular tachyarrhythmias with epidural bupiva- caine when administered for 3 days after thoracotomy.180 The aforementioned cardiovascular benefits of thoracic epidural analgesia with local anesthetics cannot be extrapolated to the use of epidural opioids or to epidural local anesthetics administered by the lumbar route. In the former instance, there is no direct inhibition of sympathetic input to the heart. In the latter, blockade of T1 to T5 would require such an extensive blockade of the sympathetic nervous system that the resultant decrease in blood pressure would very likely counteract any beneficial effects attributable to the blockade of the cardiac sympathetic fibers. The main disadvantage of epidural analgesia is that, of the regional techniques described heretofore, it is probably the most difficult to perform and is almost exclusively performed by an anesthesiologist or nurse anesthetist. Although many of these individuals have had extensive training and/or experience in performing epidurals for obstetric indications, and thus can facilely insert an epidural in the lumbar region, thoracic epidu- rals for analgesia after thoracotomy are different. Not only is the thoracic epidural space more difficult to identify owing to anatomic differences in the spinal architecture of the thoracic region, but the majority of thoracotomy patients are elderly, with calcified supra- spinous and interspinous ligaments and compressed intervertebral spaces, all of which add to the difficulty of successfully inserting an epidural. adverse effects Effects Related to Insertion of a Needle or Catheter into the Epidural Space. Adverse effects of epidural anal- gesia related to the insertion of the needle and/or catheter into the epidural space include inadvertent spinal puncture, inability to insert a needle or catheter into the epidural space, premature dislodgment of the catheter from the epidural space, temporary back pain at the insertion site, epidural hematoma, epidural abscess, and permanent neurologic deficits. The most common of these is an inadvertent spinal puncture, which occurs with an incidence of approximately 0.3 to 5%.136,181,182 Although rare, subdural hematoma and pneumocephalus have been reported after spinal puncture.182 More commonly, a medication intended for the epidural space is injected into the subarachnoid space instead, which may have disastrous consequences. An epidural dose of either local anesthetic or opioid would be clearly exces- sive in the subarachnoid space, potentially producing major motor blockade, hypotension and total spinal anesthesia with the former class of drugs, and life- threatening respiratory depression with opioids. An inadvertent spinal puncture may also produce a headache, which can be incapacitating. This postdural puncture headache may be frontal and/or occipital, usually develops 24 to 72 hours after the spinal puncture, and is due to leakage of cerebrospinal fluid through the hole in the subarachnoid membrane and subsequent traction on pain-sensitive structures at the base of the brainstem.183 It may be associated with nausea/vomiting and cranial nerve palsies and auditory disturbances,184,185 and it is clearly differentiated from other causes of headache by its prominent exacerbation with the upright position and complete resolution with the supine posi- tion. Therapy is important, not only from a humanitar- ian point of view, but because the headache may discourage the patient from coughing and assuming the upright position, thereby potentially interfering with Postoperative Analgesia for Thoracotomy Patients: A Current Review / 15
16. 16. recovery. In addition to nonopioid and opioid analgesics, more specific therapy with oral or intravenous caffeine and aggressive fluid intake instillation is usually success- ful in alleviating the postdural puncture headache. The latter is often undesirable in the post-thoracotomy patient, however. When these measures fail, instillation of 10 to 30 mL of normal saline or 20 mL of freshly obtained autologous blood (an epidural blood patch) into the epidural space, is indicated.186 The potentially catastrophic complications of epidural needle or catheter insertion, epidural hematoma and abscess, and permanent neurologic deficits are, fortu- nately, very rare. Incidence rates have been estimated to be 1 in 150,000 to 190,000,187,188 1 in 1,000 to 6,500,189191 and 1 in 3,000 to 4,500,135,192 respectively. Permanent neurologic deficits (usually paraplegia) may occur as a consequence of cord compression and ischemia induced by an epidural hematoma or abscess. Additionally, they may be related to mechanical trauma from the epidural needle or catheter, inadvertent injection of a neurotoxic substance into the epidural space, or spinal cord ischemia from other causes, such as epinephrine-induced vasocon- striction of arteries supplying the cord, pressure effect from the volume of epidural injectate, and hypotension induced by the sympathetic block.193 Epidural abscesses may arise from direct extension of infection in the local area of the epidural insertion site, or from infection at a remote part of the body, with bacteremia and subsequent seeding of the epidural space.194,195 Factors associated with the occurrence of epidural abscesses are duration of epidural catheteriza- tion 3 days190 ; immunocompromise associated with one or more complicating disease, such as cancer, acquired immunodeficiency syndrome, diabetes, multiple trauma, chronic renal failure, or chronic obstructive pulmonary disease190,195,196 ; multiple attempts at inserting the epidural needle/catheter191 ; and the use of low-dose unfractionated or low molecular weight heparin.190 The association with the latter two factors may reflect the development of a hematoma within the epidural space, which subsequently acts as a nidus for infection. Direct puncture of the extensive epidural venous plexus during epidural needle or catheter insertion may result in the development of an epidural hematoma. Although it may initially be small and clinically unimportant, this hematoma may later enlarge when the clot is disrupted by a coagulation abnormality or direct trauma. The latter may occur at any time while the catheter is being used as epidural catheters are well-known to migrate within the spinal canal.182 However, a clot is most likely to be disrupted when an epidural catheter is removed from the patient. Approximately half of the epidural hematomas attributed to epidural analgesia in Vandermeulen and colleagues 1994 review of the literature occurred immedi- ately upon removal of the epidural catheter.197 Risk factors associated with the development of an epidural hematoma include increased age,198 multiple attempts at inserting the epidural needle or catheter,198 and coagulation defects.188,198 It is controversial whether the appearance of blood in the needle or catheter during epidural insertion (known as a traumatic needle/catheter insertion) is a risk factor for the development of a significant epidural hematoma. Given the extensive vascularity of the epidural space and the 3 to 12% incidence of puncture of a blood vessel or vessels during epidural catheter insertion,182 there are obvi- ously a large number of epidural hematomas that are too small to attain clinical importance. The association between epidural hematomas and coagulation defects has been recognized for decades.197 Defects in either the platelet-mediated or coagulation factordependent phases of the coagulation system enhance the possibility of epidural hematoma formation, and combinations of defects increase the risk further.198200 Therapeutic anticoagulation with heparin, warfarin, and antifibrinolytics are known offenders, as are therapeutic and prophylactic doses of low molecular weight heparin.187,197,201 The use of NSAIDs and low-dose prophy- lactic unfractionated heparin has not been associated with a significantly increased risk of epidural hematoma formation.187,188,202 Effects Related to Epidural Injection of Local Anesthetics. Adverse effects of local anesthetics injected into the epidural space include hypotension, motor block- ade, urinary retention, and systemic toxicity. These effects are usually dose related, being most pronounced when higher concentrations of local anesthetic are used. Hypotension is a frequent occurrence as the sympathetic blockade produces peripheral vasodilation and bradycar- dia, and it is generally the limiting factor in the use of high concentrations of local anesthetic. For example, El-Baz and colleagues reported a 23% incidence of systolic blood pressure < 60 mm Hg with heart rate < 60 beats per minute in the first 24 hours after surgery, using 5 mL bolus doses of 0.5% bupivacaine administered on an as-needed basis through a thoracic epidural catheter.4 Motor block- ade of the legs interfering with ambulation is uncommon if the epidural catheter is inserted in the thoracic region.203 In contrast, weakness of the upper extremities may develop with an epidural at this level and may be distress- ing to patients.4 Urinary retention should not occur with thoracic epidurals if the volume of local anesthetic is limited to that necessary for blockade of just the thoracic dermatomes. Toxicity owing to systemic absorption is a rare occurrence at the usual recommended doses. Effects Related to Epidural Injection of Opioids. Epidural opioid adverse effects are similar to those antici- 16 / Advanced Therapy in Thoracic Surgery
17. 17. pated with parenteral administration of this class of drugs. The most frequent are nausea/vomiting, pruritus, urinary retention, and intestinal hypomotility and somnolence, and the most important is respiratory depression. Many of these effects are dose related and occur more frequently in patients who are opioid naive.204 They are usually mediated by opioid receptors, such that opioid antagonists should be effective in the prevention and treatment of these effects.205 Unfortunately, the doses of antagonist needed for this purpose may overlap with the doses that will antagonize the analgesic effects; there- fore, other treatment modalities are usually employed first, and opioid antagonists are reserved for instances when they fail. Compared with parenteral opioid admin- istration, the epidural route is associated with a greater incidence of pruritus and urinary retention, a lower inci- dence of somnolence, and an equivalent incidence of nausea/vomiting and respiratory depression.204 Pruritus, nausea/vomiting, and urinary retention occur less frequently when epidural morphine is administered as a continuous infusion than as intermittent bolus injec- tions.4 Respiratory Depression. Respiratory depression is the most feared complication of epidural opioids. Large series have reported 0.1 to 3% incidences of clinically signifi- cant respiratory depression,118,189,203,206208 defined as that requiring intervention. These represent combined data from patients having a wide variety of surgical procedures, who have received different types of medication, adminis- tered by varying protocols, through catheters inserted at both lumbar and thoracic levels of the spinal column. The incidence appears to be similar for most opioids,209 with the possible exception of an increased incidence with high bolus doses of sufentanil.210 After a single bolus dose of epidural opioid, respiratory depression classically follows two distinct patterns, which have been designated early and late.204 Early respiratory depression occurs within the first 2 to 4 hours after administration of the epidural opioid, has been observed with most opioids used during epidural analgesia, correlates with high peak plasma levels, and is thus thought to be primarily due to systemic absorption of the opioid. Late depression occurs at > 2 to 4 hours after a dose of epidural opioidmost often at 6 to 12 hours204,211 but there have been reports of respiratory depression persisting as long as 22 hours after administra- tion of a bolus dose of epidural opioid.205,212,213 This type of respiratory depression has been evidenced almost exclu- sively with morphine and is due to the rostral spread of opioid through the cerebrospinal fluid to the respiratory control centers in the brainstem. With the frequent use of infusions in recent years, the concepts of early and late have become obscured, and respiratory depression may occur at any time. Respiratory depression with epidural opioids usually presents with a slow respiratory rate, although there have been reports of severe hypercarbia with a normal respira- tory rate.214,215 In these examples, somnolence was present; hence, there is a need for the assessment of the level of consciousness as an indicator of respiratory depression. Well-established risk factors for the development of respiratory depression include older age, American Society of Anesthesiologists physical status classes III to IV, respiratory disease, sleep apnea syndrome, elevated intrathoracic pressure, and concomitant use of systemic opioids and/or other central nervous system depres- sants.118 More controversial risk factors are bolus injec- tions, compared with continuous epidural infusions154,216 ; and thoracic epidural catheters, in contrast to lumbar epidurals.118,130 The latter has been demonstrated only with morphine. Efforts to prevent postoperative respiratory depression associated with epidural opioids have focused on using the minimally effective dose of epidural opioid, limiting the quantity of all opioids and sedatives used intraopera- tively, and avoiding concomitant use of parenteral opioids and other central nervous system depressants.214 Frequent monitoring of patients for evidence of respiratory depres- sion is necessary, most often with intermittent assessment of respiratory rate and level of consciousness every 0.5 to 2 hours, plus continuous pulse oximetry. Reliance on pulse oximetry alone is not recommended as a decrease in oxyhemoglobin saturation may be a late sign of respira- tory depression when supplemental oxygen is used. Arterial blood gases and/or continuous ventilatory moni- tors may be considered for high-risk patients.215 Monitoring should be applied throughout the course of administration of the epidural opioids and continued for 4 to 6 hours after the last dose or after stopping an infu- sion.118,204 Morphine is the exception as the risk of delayed respiratory depression mandates a more protracted period of monitoring: 12 to 24 hours after the last dose has been recommended.118,182,204,205,214 The location of the monitoring has changed over the last few years. In the 1980s it was recommended that all patients with epidural opioids (with the possible exception of the obstetric population) be observed in a setting such as an intensive care unit or postanesthesia care unit.118 More recently, large series have demonstrated the apparent safety of caring for these patients on a ward, provided the staff is well educated and the aforementioned level of monitoring is maintained.189,203,208,217 Effects Related to Injection of Epidural Local AnestheticOpioid Combinations. The currently popu- lar technique of using combinations of opioids and local anesthetics to decrease the dose of each may reduce the incidence of drug-related adverse effects, although the Postoperative Analgesia for Thoracotomy Patients: A Current Review / 17
18. 18. evidence for this varies between studies. Most consis- tently, the incidence and severity of hypotension is less than that associated with local anesthetic alone,126,171,218 and the incidence of somnolence is lower than that asso- ciated with epidural opioids alone.123 At our institution we usually initiate epidural analgesia therapy with a solu- tion containing fentanyl 10 g/mL and bupivacaine 0.075% and subsequently adjust the two drugs indepen- dently, in accordance with the adverse effect profile of the individual patient. contraindications Relative contraindications to the use of epidural analge- sia include elevated intracranial pressure, preexisting disease of the spinal cord or peripheral nervous system, infection, and coagulopathy. Elevated intracranial pres- sure is listed here because of the risk of inadvertent dural puncture and subsequent brainstem herniation. With neurologic disease, there is concern that the epidural analgesia may exacerbate the underlying disease, as has been suggested for demyelinating diseases such as multiple sclerosis,219 or that a coincidental deteri- oration in neurologic function may be incorrectly attrib- uted to the epidural