Advanced therapy in thoracic surgery - part 1 pot

CHAPTER POSTOPERATIVE ANALGESIA FOR THORACOTOMY PATIENTS: A CURRENT REVIEW PETER H NORMAN, MD, FRCPC M DENISE DALEY, MD, FRCPC ALICIA KOWALSKI, MD niques for post-thoracotomy pain.2,3 Soon continuous infusions were advocated,4 and the effect of better postoperative analgesia on pulmonary function was investigated.5 This led to an increased ability to control post-thoracotomy pain and also stimulated the overall interest in finding 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 postoperative pain of most thoracotomy patients has been well handled There are occasional patients whose pain is difficult 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 unintentional 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 sympathetically mediated pain Much research is focused on treating these “new” modalities This unbundling of postoperative 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 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 admonished 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 analyses 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- Post-Thoracotomy Pain Acute Pain Pain in the first few weeks after a thoracotomy arises from a variety of different mechanisms The best characterized mechanism is somatic pain, which is localized to the area around the incision and chest tube insertion / Advanced Therapy in Thoracic Surgery 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 Visceral, or nonincisional, pain is responsible for the dull, nauseating, diffuse thoracic wall “aching” sensation experienced 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 postthoracotomy patients is localized to the ipsilateral shoulder region Although it is often moderate to severe in intensity and present in 75 to 85% of patients who have had a thoracotomy,9–11 this type of pain has received little attention in the literature It has been attributed to a variety of factors, including distraction of the posterior thoracic ligaments or shoulder joint due to patient positioning; stretching of the brachial plexus, also as a consequence 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 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 compromised respiratory function The lack of efficacy of suprascapular 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 thoracotomies (involving a transection of the latissimus dorsi muscle), some studies have demonstrated less postoperative 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 traditional thoracotomies in the early postoperative 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 to 67%.19 Dajczman and colleagues studied 59 of 206 sequential patients who had undergone a unilateral thoracotomy; all procedures were performed by one surgeon over a period of 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 months, 75% at months, and 61% after year More than 50% of these patients had limitations of their activities of daily living imposed by the chronic pain There was also a 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 problems As suggested by Perttunen and colleagues, this could TABLE 1-1 Frequency of Post-Thoracotomy Pain at Various Intervals following Surgery Time since Thoracotomy (yr) No of Patients with Pain Total No of Patients Evaluable Percentage of Evaluable Patients with Pain ≤ 1* 1–2 2–3 3–4 4–5 Total 11 3 30 12 15 13 10 56 50 73 54 50 30 — Adapted from Dajczman E et al.20 *At least months post-thoracotomy / Advanced Therapy in Thoracic Surgery 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 transdermal 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 transdermal fentanyl in the future.28 Fentanyl can be delivered across the mucous membranes 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, butorphanol, 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 analgesic Ketamine may be given by intravenous, subcutaneous, epidural (see below), oral, and transdermal routes.32 Ketamine produces analgesia by multiple mechanisms, 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 neuropathic 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 activation was the likely mechanism of the antihyperalgesia.34 Ketamine is a useful agent when narcotics and neuraxial 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 preemptive 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 postoperative 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 nonincisional 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 hypovolemic states COX-2 is thought to be inducible by inflammatory stimuli and is involved with inflammation 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 predispose to renal failure if the patient is concomitantly hypovolemic 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 ulceration but debatably to a lesser extent than conventional, Postoperative Analgesia for Thoracotomy Patients: A Current Review / nonselective NSAIDs.41–43 The selective COX-2 inhibitors 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 analgesia techniques, are very effective in blocking conduction 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 analgesia 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 irrelevant because the thoracic cavity is open intraoperatively and chest tubes are used postoperatively Finally, hypovolemia 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 extensive blockade of the sympathetic nervous system and peripheral vasodilation may be accompanied by a significant risk of hypotension, and are often avoided TABLE 1-5 Summary of Factors Related to Regional Analgesia Techniques* Technique Ease of Insertion Analgesic Efficacy Preservation of Pulmonary Function Modification of Stress Response Hypotension Motor Blockade Urinary Retention Respiratory Depression Intercostal nerve blocks +++ + + Ϫ Ϫ Ϫ Ϫ Ϫ Interpleural analgesia ± ± Ϫ Ϫ Ϫ Ϫ Ϫ Thoracic paravertebral block ++ + ++ + Ϫ Ϫ Ϫ Ϫ Epidural analgesia† + + Ϫ Ϫ ± ++ ± ++++ ++ Ϫ = 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 / Advanced Therapy in Thoracic Surgery 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 postthoracotomy 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 postoperative situations, and although the current literature regarding 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-(Ϫ)-enantiomer This contrasts with the other local anesthetics, which exist as racemic mixtures of both the R-(+)- and S-(Ϫ)-enantiomers Consequently, ropivacaine produces less cardiovascular and central nervous system toxicity,47,48 similar analgesia, and a less intense and shorter duration of motor blockade than does bupivacaine when administered into the epidural space.49,50 Low concentrations of epinephrine (1:100,000–1:400,000) are frequently added to the solution 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 variable There is even evidence that the addition of epinephrine to epidural opioid solutions may increase the incidence of some opioid-related side effects, especially pruritus.55–57 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 currently 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 prolongation of analgesic effects is accompanied by a prolongation of the duration of adverse events, which has particular relevance in the case of life-threatening cardiovascular 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 equipment, 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 intercostalis intimus muscles and is located just caudad to the intercostal artery and vein Local anesthetic is injected to 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 incisions, intercostal nerve blocks are usually performed at T3 to T7 Three to mL of local anesthetic is administered with each block; thus, a total of 20 to 25 mL of local anesthetic is used Analgesia persists for to 12 hours after a single injection,60–63 and intercostal nerve blocks may be repeated as necessary A variety of catheter techniques 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 Postoperative Analgesia for Thoracotomy Patients: A Current Review / mechanism of action Intercostal nerve blocks produce analgesia by direct blockade of the intercostal nerves There is usually minimal 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 approximately 76% of their group of patients, as measured by the lack of need for supplemental opioids 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 supplemental opioids.64–68 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 T3–T7 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 hours after surgery, pain scores during coughing were significantly lower in the intercostal nerve block group than in the other two groups No differences 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 28–62/100 at rest and 62–91/100 with coughing), and optimizing 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 surrounding area Failure to block the sympathetic chain, vagus, and phrenic nerves may further limit the ability of intercostal 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 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 postthoracotomy.8 Despite the above observations, most studies have failed to demonstrate that intercostal nerve blocks decrease the incidence of postoperative complications in post-thoracotomy patients Furthermore, although Deneuville and colleagues showed that intercostal nerve blocks were associated with fewer postoperative respiratory complications than was as-needed parenteral opioid, the incidence of complications with intercostal nerve blocks was identical to that with “fixedschedule” 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 development 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 to 20 minutes,61,64,73 and they are higher than with interpleural analgesia, TPVBs, and epidural analgesia.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 retrograde 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 injection of the local anesthetic in these circumstances contraindications There are no absolute contraindications specific to intercostal 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 / Advanced Therapy in Thoracic Surgery systemic blood levels of local anesthetic may be particularly 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 interchangeably 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 administered either as a continuous infusion or intermittent bolus doses Some authors emphasize suturing the internal 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 techniques 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 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.83–85 Interpleural analgesia has also been demonstrated to produce a degree of analgesia similar to TPVB and thoracic epidural analgesia with bupivacaine in some studies, , but less than thoracic epidural bupivacaine, lumbar epidural hydromorphone, 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 TABLE 1-6 Examples of Dosing Regimens for Interpleural Analgesia Study Intraoperative Regimen Postoperative Regimen Tartiere et al, 199181 Richardson et al, 199578 Stromskag et al, 199090 Schneider et al, 199384 Mann et al, 199282 — 10 mL 0.25% bupivacaine q8h 0.5% bupivacaine 0.1 mL/kg/h infusion 20 mL 0.375% bupivacaine prn 30 mL 0.5% bupivacaine q4h 20 mL 0.25% bupivacaine q4h 20 mL 0.5% bupivacaine q4h 0.05 mL/kg/h 2% lidocaine with 1:200,000 epinephrine infusion 20 mL 0.25% bupivacaine at chest closure — — — Silomon et al, — 200083 Raffin et al, 199485 0.15 mL/kg 2% lidocaine with 1:200,000 epinephrine after chest closure prn = according to circumstances 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 efficacy of such a maneuver has been questioned.8 Other factors that may contribute to the lack of analgesic 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 interpleural 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 surrounding 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 FEV , 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, Postoperative Analgesia for Thoracotomy Patients: A Current Review / an overall 35% preservation of function (vs the preoperative 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 equivalent, but patients receiving interpleural analgesia demonstrated significantly worse FVC and FEV1 values.78,91 This observation led to the suggestion that interpleural analgesia 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 postthoracotomy 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 postthoracotomy 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 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 traditionally 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 bronchopleural fistula or empyema; and patients for whom the effects of high systemic blood levels of local anesthetic 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, particularly 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 ligament; laterally, the posterior intercostal membrane; anteriorly, the parietal pleura; and medially, the posterolateral aspect of the vertebrae, intervertebral disk, and intervertebral 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 Subserous fascia Endothoracic fascia Pleura Visceral Parietal Esophagus Azygos vein Thoracic duct Descending aorta Sympathetic chain Interpleural space Right lung Left lung Extrapleural compartment Subendothoracic compartment Intercostal nerve Posterior primary rami Superior costotransverse ligament FIGURE 1-2 Anatomy of the thoracic paravertebral space Reproduced with permission from Karmaker MK.98 10 / Advanced Therapy in Thoracic Surgery 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 intercostal 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 percutaneously or under direct vision before the chest is closed Sabanathan and colleagues have described a technique for use during thoracotomy that involves reflecting the parietal pleura from the posterior wound margin onto the vertebral bodies to form an extrapleural pocket.99 A percutaneously 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 percutaneously placed catheter is inserted before the surgery begins and a bolus dose of local anesthetic is administered to provide intraoperative anesthesia 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 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 (range to 9) dermatomes, and a sympathetic block over an average of (range 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 anesthetize more than three to four segments A small amount of local anesthetic may also exit the intervertebral 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 opioidsparing effects have been noted in several studies comparing TPVB with placebo and parenteral opioids, 103–106 although supplemental opioids were often still necessary In comparison to epidural blockade with local anesthetics and/or opioids, TPVB has frequently demonstrated similar or better pain relief, accompanied by less nausea, vomiting, hypotension, and urinary retention.107–110 Most studies have demonstrated a significant improvement of post-thoracotomy pulmonary dysfunction with TPVB compared with placebo or parenteral opioids, as demonstrated by higher FEV , 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 function.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 (SpO ) in one study by Richardson and colleagues’ group 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 TABLE 1-7 Examples of Dosage Regimens for Thoracic Paravertebral Blockade Study Intraoperative Regimen Postoperative Regimen Carabine et al, 1995103 Catala et al, 1996101 mL 0.25% bupivacaine after chest closure — Barron et al, 1999105 0.3 mL/kg 1% lidocaine before chest closure or 0.3 mL/kg 0.25% bupivacaine before chest closure 20 mL 0.5% bupivacaine after chest closure 10 mL 0.25% bupivacaine after chest closure 20 mL 0.25% bupivacaine during chest closure 0.25% bupivacaine mL/h infusion 20 mL 0.375% bupivacaine q6h or 15 mL 0.375% bupivacaine loading dose, then mL/h 0.375% bupivacaine infusion 0.1 mL/kg/h 1% lidocaine infusion or 0.1 mL/kg/h 0.25% bupivacaine infusion Approximately 0.1 mL/kg/h 0.5% bupivacaine 3–10 mL/h 0.25% bupivacaine 0.1 mL/kg/h 0.5% bupivacaine infusion Berrisford et al, 1990111 Mathews and Govenden, 1989108 Richardson et al, 1999107 Advances in Diagnostic Imaging of the Thorax and Screening / 33 that the latest innovation of thoracic imaging, which will likely prove beneficial in oncologic imaging of the thorax, is PET/CT imaging Units acquire PET and CT images simultaneously and allow a fusion of the two studies This process allows the production of an anatomic image (CT) with a functional image (PET) as a single image Conventional Chest Radiography and PACS The chest radiograph is the most frequently performed radiographic examination, constituting > 40% of the volume of radiographs in most radiology departments In the United States alone, there are more than 50 million chest radiographs performed per year 1,2 Chest radiographs are obtained with screen film or digital methods All of these methods can produce excellent images Conventional radiography consists of a screen film system that is characterized by high spatial resolution and good uniformity However, there is a large difference between the attenuation of x-ray beams by the lungs compared with that of the mediastinal structures This difference requires a compromise between exposures for the lungs and adequate penetration for the mediastinum Several methods to improve conventional film imaging of the chest have been developed However, because these methods rely on exposure to film, the images cannot be altered once they are acquired In particular, the enhancement of a specific region of the chest cannot be performed after the image is acquired Also, while conventional methods produce excellent radiographs, they cannot be transferred into a PACS system as digital images Digital chest imaging consists of two methods: computed radiology, which uses storage phosphor plates to capture an image and require processing by a laser readout of the plate, and digital direct radiography, which uses similar detector methods but different electronics to generate an image, thus eliminating the need for a laser readout Computed radiology is commonly used for the intensive care unit because the storage plates are portable Both methods are used in dedicated chest systems One major advantage of a digitally acquired image over a conventional image is that the image quality is maintained with digital images when sent to the PACS In addition, computer programs to facilitate interpretation of images can be applied to digital images For example, dual-energy technology allows the separation of images of the lungs from the overlying bony structures This is accomplished by a rapid double exposure using high (for the lungs) and low (for the bones) energy exposures Computer software is then used to superimpose the images and to subtract the overlying structures to produce the images (Figure 2-1) FIGURE 2-1 Dual-energy chest radiograph All three images are generated at the same time A, Conventional posteroanterior view of the chest B, Soft tissue view results from subtraction of the overlying bones C, Bone view, with soft tissues removed, enhances the visualization of the ribs 34 / Advanced Therapy in Thoracic Surgery This method has been shown to improve the detection of pulmonary nodules It can also improve the detection of bony lesions Computer-aided diagnosis is a method of using computer software to prescreen radiologic images Most development of computer-aided diagnosis systems has pertained to chest radiographs, but with the generation of a large number of images using current multislice CT examination techniques, there is increasing research in the application of computer-aided diagnosis to CT Using models of standard radiology examinations, the software is trained to recognize normal anatomic structures Variations from normal structures are detected by the computer software and highlighted These guide the radiologist to review the area in question When the study is reviewed by the radiologist, a determination can be made as to whether the abnormality is a significant lesion such as a pulmonary nodule or an insignificant lesion such as a nipple shadow or artifact Computer-aided diagnosis systems have been used experimentally to detect lung nodules, interstitial lung disease, and cardiomegaly Nodule detection was improved using a computer-aided diagnosis system in retrospective clinical trials.3,4 Computed Tomography Since the clinical introduction of helical (spiral) CT in 1991, there has been dramatic improvement in image quality of CT scans of the chest This rapid imaging technique has also resulted in new applications for CT, including CT angiography for pulmonary embolism and imaging of the coronary arteries Helical CT has recently been advanced further with the introduction of multislice CT The method allows the acquisition of four channels (essentially four images) of helical data simultaneously and has reduced scanning times of the entire chest to < 20 seconds.5,6 Multichannel CT scanners continue to be developed such that eight- and 16-slice scanners will be common in the near future Because the entire chest can be imaged much faster, thinner slices can be obtained while the patient holds a single breath With thinner slices and minimal motion artifact, excellent quality three-dimensional reconstructions can be generated These prove to be beneficial when axial images are inconclusive, and they can facilitate treatment planning for therapy (Figure 2-2) The two main disadvantages of multislice CT are the increased numbers of images and higher radiation dosages to the patient.7 These disadvantages are significant because CT examinations are a large part of radiology studies In the United States alone, over 27 million CT examinations were performed in 1997, and that number is expected to increase by 10% per year.8 The large number of images results in increased costs for film printing and time for radiologists’ interpretations Because of the large number of images generated from multislice CT, a PACS is almost always required to efficiently review the images This is one of the reasons that interest in computer-aided diagnosis is increasing—these systems can preview the numerous CT images for the radiologist Magnetic Resonance Imaging MRI has been shown to be useful in the evaluation of the heart and thoracic diseases, particularly anatomy and diseases not well imaged by CT The multiplanar imaging of magnetic resonance is valuable in defining the extent of diseases of the diaphragm and soft tissues of the lung apex or superior sulcus MRI of the diaphragm is especially useful for differentiating diaphragmatic rupture from hernia in the post-traumatic setting and also for evaluating transdiaphragmatic extension in mesothelioma and other malignancies.9 MRI of the lung apex is predominately used for evaluation of superior sulcus lung cancer that may involve the brachial plexus (Figure 2-3).10 Both of these anatomic regions are not well evaluated in the axial plane of CT Variations in the signal of magnetic resonance are also useful in characterizing masses in the chest, such as assessing whether lesions are cysts or hematomas These signal characteristics can be used to distinguish between simple fluid, blood products, and solid masses Tumor assessment in the mediastinum predominantly includes determining the origin of the tumor and what adjacent structures may be involved Recent advances in MRI include the development of rapid acquisition sequences that provide cardiac gated images during breath holding Such rapid acquisitions minimize motion artifacts, resulting in an improved demonstration of anatomic details Black blood sequences use an extra radiofrequency pulse to suppress the signal from the blood pool.11,12 These images can be obtained in a single breath hold of about 10 seconds and give excellent detail at a single phase of the cardiac cycle White blood images are obtained more rapidly at the cost of decreased resolution and increased noise (Figure 2-4).13 An image series is obtained in a 10-second breath hold, consisting of 20 phases of the cardiac cycle at a single level Cine display of these images shows the relationships between moving structures in the heart This is particularly useful to show valve motion to demonstrate whether the valve leaflets have tumor involvement or their motion is impaired by tumor or distortion of the cardiac structures The cine display can also demonstrate ventricular wall motion abnormalities from prior infarcts In addition, these images can be used to calculate functional parameters, 38 / Advanced Therapy in Thoracic Surgery crescent does not enhance Atherosclerotic ulcerations are typically in the descending thoracic aorta and appear as localized defects of the intima.22 Aortography remains the “gold standard” for evaluation of the aorta in the trauma patient However, because helical CT is quicker and easier to obtain and is less invasive, it has become the imaging modality of choice in many centers Several large series have shown that in certain clinical settings, CT angiography is as effective as aortography for evaluation of the aorta 23–26 Further refinement and application of techniques in this clinical setting using multislice CT will most likely improve acceptance of CT angiography as the preferred method of evaluation of the aorta in the trauma patient The evaluation of a patient for pulmonary embolus and deep venous thrombosis remains a difficult proposition Imaging of the patient includes ventilationperfusion scanning, pulmonary angiography, computed FIGURE 2-6 Aortic dissection Helical computed tomography scan shows a dissection of the descending aorta (arrow) Note the secondary finding of a hemorrhage into the left pleura tomographic angiography and venography, and ultrasonography Although there are many algorithms for using these imaging modalities and there is no agreement as to which is best, there is a general agreement that advancements in multislice CT have significantly improved the ability of computed tomographic angiography to detect pulmonary embolus.27 The initial application of CT as the primary imaging modality for diagnosing pulmonary embolus was performed by Remy-Jardin and colleagues.28 They concluded that CT was a safe and complementary procedure to angiography for evaluation of a suspected pulmonary embolus Detection of acute pulmonary emboli to the segmental artery branch has subsequently been reported to have a sensitivity range of 53 to 100% and a specificity of 81 to 100%.29 In many institutions helical CT angiography is the primary method for evaluation of a pulmonary embolus because it is readily available, rapid, and essentially noninvasive and therefore safe Multiplanar images can also be produced rapidly to facilitate evaluation for pulmonary embolus (Figure 2-7) Contributing to the rapid acceptance of CT for embolus evaluation is the high frequency of detection of other significant disease in the chest It has been reported that up to 67% of patients without pulmonary embolus have other significant disease found on CT evaluations for pulmonary embolus.30 Large, randomized, and controlled collaborative studies are planned to further evaluate CT in the diagnosis of pulmonary embolus Until then, the popularity of computed tomographic angiography for pulmonary embolus will increase and likely become the imaging study of choice In patients with contraindications to IV iodine-based contrast material, rapid sequence MRI and contrast (gadolinium)-enhanced MR angiography allow excellent evaluation of the aorta and pulmonary vessels MRI also provides multiplanar evaluation and physiologic assessment of blood flow Detection of pulmonary embolus with MRI has been reported to have a sensitivity of 90 to 100% and a specificity of 62 to 77%.31,32 Unfortunately, MRI has not been successful in detecting peripheral emboli beyond the subsegmental artery branch level, even with administration of a contrast medium.33,34 Lung Cancer Screening It is well known that the majority of patients with lung cancer present with symptoms that indicate an advanced stage at diagnosis.35 In an effort to detect lung cancer earlier, four randomized, controlled studies have been performed: the Memorial Sloan-Kettering Lung Project, the Johns Hopkins Lung Project, the Mayo Lung Project, and the Czechoslovak study.36–41 Although different in 40 / Advanced Therapy in Thoracic Surgery clinically milder disease and better prognosis.47 Recent reports by two separate groups have also shown that lowdose helical CT in high-risk patients can detect lung cancers at an earlier stage than can conventional chest radiography The Anti-Lung Cancer Association, a group in Japan, has screened 1,369 patients who were considered at high risk for lung cancer by performing annual helical CT using low dosage to limit radiation exposure (low-dose helical CT) This study showed that CT was superior to chest radiography for detecting peripheral lung cancer Of 15 lung cancers detected by CT, only 11 cancers were detectable with chest radiography Fourteen (93%) of the 15 cancers were at stage I 45 The Early Lung Cancer Action Project is a study performed in the United States that also used low-dose helical CT to screen for lung cancer in 1,000 patients who were at high risk for lung cancer Malignant disease was detected in 2.7% using CT but in only 0.7% with chest radiography Of the 27 lung cancers detected by CT, 23 were at stage I Only (0.4%) of the lesions detected by chest radiography were at stage I.48 In both groups, high-risk patients were defined as those with a significant cigarette smoking history and no previous malignancy FIGURE 2-8 Spiral computed tomography scan shows a mm adenocarcinoma (arrow) that was not evident on a chest radiograph However, there is much debate about the effectiveness of CT screening on the overall impact of lung cancer, in particular, disease-specific mortality.49–51 In an attempt to further evaluate the effectiveness of low-dose helical CT for lung cancer, a large, randomized controlled study is being funded by National Cancer Institute After starting in September 2002, the trial enrolled 50,000 participants by February 2004 Follow-up analysis is being performed with completion of the study targeted for 2009.This trial compares low-dose helical (spiral) CT to chest radiographs for screening cancer Quality of life, smoking cessation, smoking addiction, and biomarkers are also part of this trial Evaluation of the Solitary Pulmonary Nodule The solitary pulmonary nodule remains one of the most, if not the most, difficult diagnostic problems in radiology Most of the advances in imaging have resulted in an increased ability to detect a solitary pulmonary nodule, but characterization of the lesion often requires longterm surveillance or biopsy There are numerous etiologies for such nodules, with the large majority consisting of a malignant nodule, a benign nodule, or an infection.52 With the renewed interest in lung cancer screening with CT, it is anticipated that the magnitude of this diagnostic dilemma will greatly increase In the 1950s and 1960s, reports concerning solitary pulmonary nodules in the general population attributed < 5% of cases to cancer.53 In patients referred for resection of the nodules, the malignant lesions represented approximately 40% of cases and granulomas another 40%.54 More recent data concerning resected nodules shows that single pulmonary nodules represent malignancies in up to 60% of cases.54,55 This is attributed to the consideration of benign lesions being eliminated with CT imaging Newer imaging techniques including helical CT and PET have improved the predictability of a lesion representing a malignancy However until an ideal radiologic imaging technique is developed that eliminates benign lesions, radiologist will depend on existing criteria for determining a benign lesion Even with exciting advances in imaging modalities, the evaluation of the solitary pulmonary nodule still begins with the morphologic evaluation of the lesion This includes an evaluation of the size, edge characteristics, rate of growth, and calcification Whereas there are a few radiologic features of benign lesions, there is no specific radiologic feature for a malignant lesion Therefore, based on radiologic criteria, a solitary pulmonary nodule is classified as a benign or an indeterminate nodule Despite being limited to morphologic evaluation, multislice CT advances have improved our ability to evaluate a solitary pulmonary nodule This is predominately Advances in Diagnostic Imaging of the Thorax and Screening / 41 because of the ability to image the chest rapidly during a single breath hold The end result is less motion artifact and thinner-slice images, which improve characterization compared with single-slice CT size Lesions cm or larger are most likely to be malignant, but this size criterion is not useful in assessing a solitary pulmonary nodule Size criteria for potential malignancy was initially based on chest radiograph findings, but more recent CT studies showed that the malignant potential of small lesions detected by CT was significant.55,56 CT examinations also detect smaller lesions better than does conventional chest radiography, and an increase in detection of small lesions will occur as the use of multislice CT increases Although size is not reliable for characterization, it should be noted that some lesions that were indeterminate on chest radiographs have been proven benign with CT Therefore, lesions that remain indeterminate by CT have a greater chance of being malignant edge characteristics There is no characteristic appearance of the edge of a nodule that indicates a malignant lesion However, the interface that a nodule makes with the adjacent lung can suggest a greater probability for a malignant lesion than a benign one Although these edge characteristics have been reported to be more indicative of a malignant nodule, they also occur in benign lesions Nonetheless, in the management of a nodule, assessment of the edge characteristics has value A lobulated border of a nodule is reported to be predictive of a malignant lesion in over 80% of cases (Figure 2-9).57 Spiculated margins or linear striations extending from the margins of the lesion into the parenchyma are often seen in malignant lesions and are therefore highly suggestive.58,59 The spicules can reflect extension of the tumor into the parenchyma or a reaction of the parenchyma to the tumor Unfortunately, this reaction can occur in benign lesions such as granulomas; therefore, this appearance is useful but not diagnostic An extension of one of these spicules of a peripherally located lesion to the pleural surface has been termed the pleural tail sign and was thought to be indicative of a malignancy (Figure 2-10) However, this sign has been proven unreliable because it is seen in malignant and benign lesions, particularly granulomas.58,60–62 The presence of a patent bronchus leading into a peripheral lesion was called the bronchus sign by Kuriyama and colleagues and was reported to have an association with adenocarcinoma.63 However, a patent bronchus or air bronchogram is more commonly seen in benign lesions The value of a bronchus sign may lie in the fact that it is useful in predicting a successful sampling by transbronchial biopsy.64 FIGURE 2-9 Multislice computed tomography scan shows a lobulated mass of the right lower lobe that proved to be squamous cell carcinoma FIGURE 2-10 Computed tomography scan of a left upper lobe squamous cell carcinoma Note the spicules of the tumor borders and the linear extension (pleural tail) that extends to the pleural surface 42 / Advanced Therapy in Thoracic Surgery rate of growth To adequately assess a lesion for an interval change in growth, it is necessary to obtain the appropriate prior radiograph for comparison, an exercise that is becoming more difficult with the transient nature of our society and the influence of managed care contracts As noted previously, it is hoped that digital imaging and Webbased distribution of images will greatly help the clinician to provide this comparison for patients Radiologic assessment of nodule stability was first published by Good and Wilson in 1958 In this article they introduced the concept that years of stability of a lesion on chest radiographs implied a benign process.65 Since then, this concept has become radiology dogma, based on studies reporting that the majority of malignant nodules double in volume between 20 and 400 days.66,67 A nodule that doubles in size in < month is probably infectious, and one that takes 18 months or longer to double is usually benign.68 Exceptions to these guidelines are slow-growing adenocarcinoma and carcinoid tumors that take years to double in size, and the development of hemorrhage in a malignant lesion that results in a rapid increase in size Additionally, some malignancies grow more rapidly than expected (Figure 2-11) Despite these exceptions, the evaluation of doubling times of pulmonary nodules remains useful in establishing the diagnosis of a solitary pulmonary nodule calcification The most reliable radiologic characteristic to differentiate a benign from a malignant lesion is the presence or absence of calcification Calcification is usually indicative of a benign lesion; however, more important than its presence is the pattern of calcification Characteristically benign patterns include lesions that are totally calcified, densely calcified, or laminated in appearance When a bronchogenic carcinoma calcifies, the pattern is usually stippled or eccentric 69 Eccentric calcification occurs when a malignancy engulfs a calcified granuloma (Figure 2-12) Some metastatic nodules can exhibit calcification, but these are usually multiple and in the appropriate clinical setting Calcification is best evaluated with CT,55 but digital radiography with dual-energy subtraction may prove to be as useful.70 “ditzels” Because of the improvement in image quality with the increase in helical CT use, there has been a rise in the detection of tiny nodules, such that it is common to see mm nodules on CT scans Of course, these nodules are too small to characterize and therefore present diagnostic and management dilemmas; as a result, these are often referred to as “ditzels.” What is to be done with these tiny nodules? 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high-resolution CT and radiologicpathologic correlation Radiology 1991;179:469–76 59 Huston J III, Muhm JR Solitary pulmonary opacities: plain tomography Radiology 1987;163:481–5 60 Bryk D The participating tail A roentgenographic sign of pulmonary granuloma Am Rev Respir Dis 1969;100:406–8 61 Hill CA “Tail” signs associated with pulmonary lesions: critical reappraisal AJR Am J Roentgenol 1982;139:311–6 62 Shapiro R, Wilson GL, Yesner R, Shuman H A useful roentgen sign in the diagnosis of localized bronchioloalveolar carcinoma Am J Roentgenol Radium Ther Nucl Med 1972;114:516–24 46 / Advanced Therapy in Thoracic Surgery 63 Kuriyama K, Tateishi R, Doi O, et al Prevalence of air bronchograms in small peripheral carcinomas of the lung on thin-section CT: comparison with benign tumors AJR Am J Roentgenol 1991;156:921–4 64 Gaeta M, Pandolfo I, Volta S, et al Bronchus sign on CT in peripheral carcinoma of the lung: value in predicting results of transbronchial biopsy AJR Am J Roentgenol 1991;157:1181–5 65 Good CA, Wilson TW The solitary circumscribed pulmonary nodule: study of seven hundred five cases encountered roentgenologically in a period of three and one-half years JAMA 1958;166:210–5 66 Steele JD, Buell P Asymptomatic solitary pulmonary nodules Host survival, tumor size, and growth rate J Thorac Cardiovasc Surg 1973;65:140–51 67 Weiss W Peripheral measurable bronchogenic carcinoma Growth rate and period of risk after therapy Am Rev Respir Dis 1971;103:198–208 68 Nathan MH, Collins VP, Adams RA Differentiation of benign and malignant pulmonary nodules by growth rate Radiology 1962;79:221–32 69 Mahoney MC, Shipley RT, Corcoran HL, Dickson BA CT demonstration of calcification in carcinoma of the lung AJR Am J Roentgenol 1990;154:255–8 70 Fraser RG, Hickey NM, Niklason LT, et al Calcification in pulmonary nodules: detection with dual-energy digital radiography Radiology 1986;160:595–601 71 Swensen SJ, Brown LR, Colby TV, Weaver AL Pulmonary nodules: CT evaluation of enhancement with iodinated contrast material Radiology 1995;194:393–8 72 Patz EF Imaging lung cancer Semin Oncol 1999;26:21–6 CHAPTER TISSUE ADHESIVES IN THORACIC AND CARDIOVASCULAR SURGERY ROSS M REUL, MD GARRETT L WALSH, MD body reactions If blood products are used, the risk of viral transmission must be minimized Tissue adherence must be rapid and strong, but the adhesive must not penetrate deeply into tissues Tissue adhesives must remain flexible after polymerization, especially when used on dynamic pulmonary, cardiac, or vascular tissues For decades surgeons have been using tissue adhesives as an adjunct to conventional surgical techniques for a variety of indications Improvements in the safety and availability of tissue adhesives have led to their widespread use With increasing experience and the development of newer compounds and modifications to existing tissue adhesives, the number of potential applications will continue to grow The ideal tissue adhesive has not yet been developed, and until this happens, the properties of each type will determine its usefulness for particular situations An understanding of the various properties and mechanisms of action of the available compounds therefore helps surgeons decide when to use one of these adhesives and which is the most appropriate for each clinical situation Tissue adhesives are most commonly used to enhance hemostasis Tissue adhesives are also being used increasingly to seal or prevent air leaks after thoracic surgery Their use to seal friable tissues in the repair of acute type A aortic dissections is also becoming routine Tissue adhesives have been used in desperate situations to seal subacute ruptures after myocardial infarctions and to close bronchopleural fistulas Some agents are used to prevent postoperative adhesion formation Tissue adhesives are also used as carriers for the slow, local release of antibiotics, chemotherapeutic agents, or other medications, and they hold promise for the delivery of gene therapy For a tissue sealant to be clinically useful, it must be safe and effective Preparation time, ease of delivery, and cost are also important considerations Tissue adhesives and their products of degradation must also be nontoxic, noninfectious, nonimmunogenic, and noninflammatory They should promote—and must not impede—healing The materials must be biodegradable to avoid foreign Historical Perspective Fibrin sealants, also known as fibrin glues, are the most widely used and extensively studied tissue sealants currently in use Commercially available fibrin sealants are composed of fibrinogen, thrombin, calcium chloride, and usually an antifibrinolytic such as aprotinin Bergel first used fibrin as an experimental hemostatic agent in 1909 Others used fibrin-impregnated materials to control parenchymal bleeding 2,3 The combination of fibrinogen and thrombin to anchor skin grafts was first used clinically in 1944,4 but the lack of concentrated fibrinogen limited its adhesive strength The risk of hepatitis transmission associated with its use also complicated its application Techniques to provide concentrated and purified human fibrinogen allowed for more reproducible results.5 Cyanoacrylate was used as a hemostatic agent in the 1960s and to seal pulmonary tissue after recurrent spontaneous pneumothorax in 1967.6,7 However, extensive tissue reaction and toxicity prevented the widespread clinical use of this synthetic tissue sealant Cyanoacrylate derivatives are currently used externally as skin adhesives.8 Matras and colleagues used cryoprecipitated plasma with a high fibrinogen concentration combined with bovine thrombin to create a fibrin sealant for reuniting transected peripheral nerves in rabbits in 1972.9 Fibrin 47 48 / Advanced Therapy in Thoracic Surgery sealant was subsequently used in human nerve anastomoses using autologous and then single-donor plasma cryoprecipitate combined with bovine thrombin in 1974 10 Fibrin sealant was then used as a hemostatic adjunct for repairing bleeding parenchymal lesions.11,12 Spangler first used fibrin sealant in cardiovascular surgery in 1976.13 In 1978 Akrami and colleagues used fibrin glue to preseal polyethylene terephthalate fiber (Dacron, L R Bard, Tempe, AZ) prosthetic grafts 14 Koveker and colleagues expanded the use of fibrin sealants to include the control of bleeding from polytetrafluoroethylene graft suture lines and coronary artery anastomoses and from myocardial and cardiac venous bleeding sites.15 In 1982 Borst and colleagues reported a 95% success rate using fibrin sealant as a hemostatic agent in 340 patients undergoing cardiac surgical procedures with cardiopulmonary bypass.16 They used commercially available fibrinogen (Tissucol, Immuno AG, Vienna, Austria) combined with bovine thrombin, calcium chloride, and aprotinin applied to collagen fleece or delivered by a dual-syringe system.16 Despite the increasing use of fibrin sealants in Europe and Japan, early experience was limited in the United States because the US Food and Drug Administration (FDA) revoked the approval of fibrin human fibrinogen concentrates in 1978 owing to the risk of viral transmission through the use of human donor plasma products Rousou and colleagues,17 with investigational approval by the FDA, conducted a multicenter, prospective, randomized, controlled clinical trial comparing fibrin sealant (Tisseel, Immuno AG) with conventional topical hemostatic agents for patients undergoing cardiac reoperations in 1989 They reported improvements in the time required for complete hemostasis, the amount of postoperative blood loss, and re-sternotomy rates17 in the fibrin sealant group Although experience with commercially manufactured fibrin sealants continued to be gained outside the United States, American surgeons were using fibrinogen from autologous plasma and local blood bank sources.18,19 The theoretic risk of virus transmission from donor plasma sources prompted the development of synthetic and nonhuman-derived biologic tissue adhesives Gelatinresorcinol-formaldehyde (GRF) glue, also known as “French glue,” has been used for many years in Europe for reinforcing the layers of the aortic wall during the repair of aortic dissections GRF glue and a modification (gelatinresorcinol-formaldehyde-glutaraldehyde [GRFG] glue) have also been used for hemostasis and for sealing air leaks, with mixed results Concerns about the in vivo toxicity of formaldehyde have kept these agents from gaining FDA approval BioGlue Surgical Adhesive (CryoLife, Inc., Kennesaw, GA) is composed of bovine serum albumin and 10% glutaraldehyde It is a less toxic alternative to GRF glue and has been approved by the FDA for use in the repair of thoracic aortic dissections and hemostasis It has also shown utility in sealing pulmonary air leaks, but there are currently no clinical data in the literature to support the use of BioGlue in this setting FocalSeal-L (Genzyme Biosurgery, Cambridge, MA) is a polyethylene glycol hydrogel that is photopolymerized after tissue application It is currently the only tissue adhesive that is FDA approved for use in lung surgery to seal air leaks Although experimental evidence has shown its utility as a hemostatic agent, proper application in the presence of bleeding can be challenging FloSeal Matrix (Fusion Medical Technologies, Inc., Mountain View, CA) is a combination of gelatin and collagen that has recently been approved as a hemostatic agent CoSeal surgical sealant (Cohesion Technologies Inc., Palo Alto, CA) is a hydrogel composed of polyethylene that has been approved as a vascular sealant to enhance hemostasis at the suture lines of prosthetic grafts when applied before releasing the cross-clamps CoStasis (Cohesion Technologies) is a hemostatic agent that uses autologous TABLE 3-1 FDA-Approved Tissue Adhesives Trade Name* Components Adjuncts to hemostasis Hemaseel APR Tisseel VH BioGlue FloSeal CoSeal CoStasis Human fibrinogen, human thrombin, bovine aprotinin, CaCl Human fibrinogen, human thrombin, bovine aprotinin, CaCl Bovine serum albumin, glutaraldehyde Bovine thrombin, collagen-gelatin matrix Two-component polyethylene glycol Autogenous fibrinogen and platelets, bovine thrombin, collagen Pulmonary sealant FocalSeal-L Polyethylene glycol (photocross-linked with xenon light source) External wound closure Dermabond (Closure Medical Corporation, Raleigh, NC) 2-octyl-cyanoacrylate FDA = US Food and Drug Administration *See text for manufacturer details Tissue Adhesives in Thoracic and Cardiovascular Surgery / 49 plasma, including platelets and fibrinogen, combined with bovine thrombin and bovine collagen Although experimental and early clinical studies have shown the efficacy of each of these newer agents, long-term studies and large, randomized clinical trials are lacking Hemostatic Agents and Vascular Sealants Tissue adhesives currently approved for use as adjuncts to enhance hemostasis include the fibrin sealants Tisseel VH (Baxter Healthcare Corp., Deerfield, IL) and Hemaseel APR (Haemacure Corp., Montreal, PQ), FloSeal, BioGlue, CoSeal, and CoStasis (Table 3-1) Each has unique properties that must be considered when using these agents clinically The fibrin sealants, as noted already, have been studied extensively for a wide range of indications, with reported efficacy and safety Long-term clinical follow-up data are not yet available for FloSeal, BioGlue, CoSeal, or CoStasis Other adhesives used clinically for hemostasis, but not approved for this use by the FDA, include GRF glue, FocalSeal-L, and cyanoacrylate The advantage of a fibrin sealant is its biocompatibility The components and packaging of Tisseel VH and Hemaseel APR are similar Each is supplied as two separate vials, one containing human fibrinogen and bovine aprotinin and the other containing human thrombin and calcium chloride The two vials are reconstituted separately and delivered using a dual-syringe system to apply equal volumes of each to the target tissue (Figure 3-1) The delivery systems include blunt-tip applicators for direct application or spray tips for more diffuse areas of coverage (see Figure 3-1) Fibrin sealant is designed to mimic the final stage of the coagulation cascade In the presence of calcium ions, thrombin catalyzes the conversion of fibrinogen to fibrin and activates factor XIII in the plasma Activated factor XIII then mediates the cross-linking of fibrin monomers to polymerize the clot This occurs within seconds to minutes after the two components of fibrin sealant combine at the target site in vivo Aprotinin is included to inhibit fibrinolysis, resulting in more prolonged clot stability (Figure 3-2) The tensile strength of the resultant clot is determined by the fibrinogen concentration, and the rate of clot adherence is determined by the concentration of thrombin The use of fibrin sealants derived from autologous plasma and local blood bank cryoprecipitates has been reported to achieve good results, but the concentrations of fibrinogen and thrombin may be less reproducible than those achieved in the commercially prepared products The largest controlled study of the use of fibrin sealants in cardiothoracic surgery was a multicenter, prospective, randomized trial reported by Rousou and colleagues in 1989.17 At 11 US centers, 333 patients were studied who underwent reoperation for cardiac surgery or emergency re-sternotomy within 24 hours after cardiac surgery Patients with bleeding that was not controllable with conventional suture techniques were randomized to treatment with fibrin sealant (Tisseel) or with conventional topical hemostats, including Avitene (Avicon, Inc., Humacao, Puerto Rico), Gelfoam (Johnson & Johnson Products, Inc., New Brunswick, NJ), Oxycel (Deseret, Sandy, UT), Surgicel (Upjohn Company, Needham Heights, MA), and Thrombinar (Armour Pharmaceuticals, Tarrytown, NY) The fibrin sealant was applied either directly to the bleeding site with a dualsyringe applicator or onto a Helistat (Citagenix Inc, Laval, PQ, Canada) carrier that was applied to the target site The end point of the randomized portion of the study was the cessation of bleeding within minutes of FIGURE 3-1 Tisseel-VH Duploject applicator (A) and Fibrinotherm heating and stirring device (B) The dual-syringe system allows the two components of the fibrin sealant to remain separated until direct application to the target tissue (Courtesy of Baxter Healthcare Corp.) Tissue Adhesives in Thoracic and Cardiovascular Surgery / 51 100 ** ** * 75 50 25 Redo Control Re-sternotomy Fibrin Sealant Total * p < 005 ** p < 001 FIGURE 3-3 Percentage of hemostatic success within minutes for patients with fibrin sealants versus controls Adapted from Rousou J et al.17 p 199 had failed In the nonrandomized portion of the study, there was no statistically significant difference between the groups in terms of chest tube drainage 12 hours postoperatively The quantity of drainage fluid was 740 mL in the fibrin sealant treatment group versus 819 mL in the matched historical control group (p = 348) However, when the number of patients in whom more than 1,499 mL of fluid drained in the first 12 hours postoperatively was analyzed (in only 56 matched pairs with these data available), there was a significant difference (fibrin sealant 1.8% versus control 14.3%, p < 05) There were also no significant differences in re-sternotomy rates (fibrin sealant 4.5% versus control 6.8%), hospital stays (fibrin sealant 12 d versus control 12.9 d), or blood products transfused (odds ratios for no blood products transfused: fibrin sealant 0.9 versus control 1.1) (Figure 3-4) When the fibrin sealant group was compared with nonmatched historical controls, there was no significant difference in operative mortality.17 Despite its limitations, 15 * 10 Blood Loss Re-sternotomy (%) Hospital Stay (d) > 1,499 cc/12 h (%) Blood Products (Odds) End Points Control Fibrin Sealant * p < 05 FIGURE 3-4 Various end points for patients receiving fibrin sealant versus historical matched controls Adapted from Rousou J et al.17 p 199 this study has been extensively referenced as evidence of the benefits of fibrin sealants as topical hemostatic agents Spotnitz and colleagues sprayed fibrin sealant over the anterior mediastinum before closing the sternum in 20 patients undergoing cardiac operations and reported a decrease in average chest tube output compared with matched controls at 12 hours (461 mL vs 731 mL, respectively; p < 05) and 24 hours postoperatively (714 mL vs 1,016 mL, respectively; p < 05) Matthew and colleagues used single-donor concentrated fibrinogen and bovine thrombin applied by individual syringes, spray applicators, or endoscopic cannula delivery in 634 cardiac operations and reported a 94% success rate in controlling bleeding as assessed by the surgeon.21 Other clinical studies with small cohorts of patients have shown decreased chest tube drainage after reoperative cardiac surgery and congenital heart surgery.22,23 The greatest advantage of fibrin sealant over other available tissue adhesives for hemostasis in cardiothoracic surgery is the lack of serious complications associated with many years of its clinical use involving several million applications 24 The fibrin clot resulting from fibrin sealant is degraded by natural fibrinolysis and phagocytosis and is completely broken down within to weeks Studies have shown minimal inflammatory reaction to the clot other than routine wound healing mechanisms Adhesion formation and fibrosis at the site of experimental application have been shown to resolve within to months Human fibrinogen and thrombin in Tisseel VH and Hemaseel are obtained from human donors; therefore, the potential exists for viral transmission However, donors undergo a rigorous screening process, and the plasma is screened for hepatitis B and C viruses and human immunodeficiency virus (HIV) The human components then undergo a two-step vapor heating viral inactivation process Of the ≥ million applications reported, there have been no confirmed cases of the transmission of viral hepatitis or HIV from the use of fibrin sealant.24 There have been some cases reported of transmission of parvovirus B19 infection,7 however, and one of the limitations of the viral inactivation process is that it is not effective against nonenveloped viruses The most serious complications reported to date have been immunologic responses to bovine antigens or to impurities present in earlier preparations of fibrin sealants Inhibitory antibodies to thrombin and factor V have developed in a few patients after treatment with local fibrin sealant containing bovine thrombin and aprotinin.25–28 The fibrin sealants currently available for hemostasis use bovine aprotinin, not human thrombin and fibrinogen Although the risk of immunologic 52 / Advanced Therapy in Thoracic Surgery response to locally applied aprotinin exists, the incidence remains quite low and is usually associated with repeat exposures All tissue adhesives used for hemostasis have the potential to produce thrombotic complications.29 In clinical use, however, thrombogenic events are rare and are most often associated with intraluminal contamination with the tissue adhesive CoStasis is an FDA-approved hemostatic agent that uses autologous plasma as a source of fibrinogen The apparatus includes a centrifuge kit for autologous plasma that can be obtained before or after heparinization.30 Bovine thrombin and fibrillar bovine collagen are prepared in one syringe and fibrinogen in a second syringe When applied in situ using a dual-syringe applicator, the sealant polymerizes into a stable clot Similar to fibrin sealant, CoStasis can be delivered directly with a blunt-tip applicator or sprayed diffusely to cover larger areas The mechanism of action is similar to that previously described for fibrin sealants Its advantage is the avoidance of donor human plasma as the source of fibrinogen In a study of the effectiveness of CoStasis as a hemostatic agent in experimental rabbit spleen and kidney injuries, the application of CoStasis resulted in more complete and more rapid hemostasis than did fibrin sealant or collagen sponge treatment The efficacy was maintained after platelet or fibrinogen depletion Turner and colleagues showed more rapid control of bleeding in sheep liver, spleen, and kidney injuries with the use of CoStasis than with a fibrin sealant (p < 005) or a collagen sponge (p < 013).30 In heparinized sheep, the hemostasis times were similar between CoStasis and the fibrin sealant, but the overall blood loss was less in the CoStasis group A randomized, controlled, multicenter study compared the use of sprayable CoStasis in 167 patients versus 151 control patients undergoing general, hepatic, cardiac, and orthopedic operations at 10 US medical centers.32 Hemostasis with collagen or gauze sponges was attempted in the control patients Overall, hemostasis was achieved within 10 minutes in 92% of the CoStasis group compared with 58% in the control group (p = 01) In the cardiac surgical cohort, CoStasis treatment resulted in hemostasis within 10 minutes in 28 of 37 patients (76%) versus 17 of 37 patients (46%) in the control group (p = 02) The time to controlled bleeding and the time to complete hemostasis were also superior in the CoStasis arm of each surgical specialty investigated.32 CoStasis has also been used clinically to achieve more rapid and complete hemostasis of sternal edges and iliac bone grafts than was accomplished with conventional surgical techniques.33 Although CoStasis may be an alter- native to the use of donor plasma–derived fibrin sealants, the risk of immunologic reactions to bovine antigens remains, and clinical experience and long-term data are lacking Preparation time and cost must also be factored into the clinical equation FloSeal Matrix consists of granular bovine collagen that is premixed with bovine thrombin and then delivered topically to a bleeding site The granular collagen swells to tamponade bleeding, and the thrombin promotes local clot formation The clot is reabsorbed naturally within to weeks FloSeal has been used as a hemostatic agent in peripheral vascular surgery with good results in a small number of patients.34 A recent multicenter, prospective, randomized clinical trial compared 93 patients undergoing cardiac operations treated with either FloSeal or Gelfoam-Thrombin to control bleeding sites.35 In the FloSeal group, 48 patients had 104 bleeding sites treated, and in the Gelfoam-Thrombin group, 45 patients had 61 bleeding sites treated Hemostasis was achieved within 10 minutes in 88% of the bleeding sites treated with FloSeal versus 57% treated with Gelfoam-Thrombin (p < 001) (Figure 3-5) The time to hemostasis was also shorter in the FloSeal group (p < 001).35 The advantages of this preparation include its ability to conform geometrically to the bleeding site, rapidity of preparation, and ease of delivery CoSeal was approved by the FDA for use as a vascular sealant in December 2001 It is packaged as a dualsyringe system containing two distinct types of polyethylene glycol that polymerize rapidly into a clear hydrogel The low-viscosity gel conforms to surrounding tissues, then polymerizes within seconds and adheres to tissues and vascular grafts to create a strong, flexible seal The hydrogel is biodegradable and is broken down after to weeks Unique among the hemostatic agents previously discussed, CoSeal contains no human or animal plasma products (Figure 3-6) Experimental studies have shown CoSeal to be effective in controlling suture hole bleeding at vascular graft anastomotic sites.36,37 In a multicenter, randomized, controlled clinical trial, CoSeal was compared with Gelfoam-Thrombin for hemostatic effectiveness in patients undergoing peripheral vascular surgery using polytetrafluoroethylene grafts.38 Seventy-four patients had anastomotic bleeding sites sealed with CoSeal, with a 10-minute sealing success rate of 86% versus 80% in 74 patients treated with Gelfoam-Thrombin (p = 29) However, immediate sealing (p < 001) and the time required for complete sealing (p = 01) were better in the CoSeal group.38 CoSeal is currently approved as a vascular sealant as opposed to a hemostatic agent It should be applied to vascular anastomoses in a dry field, avoiding sites of active bleeding This often requires either prophylactic use before 54 / Advanced Therapy in Thoracic Surgery closure, with or without reinforcement, offers any benefit in reducing the occurrence or duration of air leaks.42,44–47 Authors have advocated the use of water seal over suction and the early removal of chest tubes to decrease small air leaks and infection rates.42,48 Prolonged air leaks are seen in as many as 15% of patients after elective pulmonary resections and as many as 50% of patients after pulmonary volume reduction.42,49 Tissue sealants have been used as an adjunct to conventional surgical techniques in an attempt to decrease the incidence and duration of postoperative air leaks Fibrin sealants have been used as pulmonary sealants for 20 years but with inconsistent results.50–58 This failure has been attributed to the relatively low tissue adherence of fibrin sealants Tissue adhesives such as cyanoacrylate and GRF glue result in more extensive tissue adherence but may further injure the dynamic pulmonary tissue with volume changes Also, the toxicity of these agents has precluded their routine use in pulmonary surgery.59,60 A recent experimental study in sheep showed that BioGlue was effective as an adjunct to conventional surgical techniques in sealing bronchial anastomoses and pulmonary parenchymal defects.60 FocalSeal-L is currently the only tissue sealant that is approved by the FDA to seal or prevent air leaks It can also be used as an adjunct to staples or sutures to seal pulmonary parenchymal closures It is not currently recommended for use on bronchial anastomoses or stumps FocalSeal-L is a synthetic, water-soluble, bioabsorbable hydrogel A primer composed of polyethylene glycol is first brushed onto the target site to prepare the tissue for adhesion The sealant polymer is then gently brushed into the primer for mixing A second layer of sealant is then applied over the target site in a thin layer A xenon light wand is used to photopolymerize the sealant to solidify the gel (Figure 3-7) After polymerization the gel is adherent and elastic, which allows it to accommodate the dynamic nature of the lung In experienced hands the application process takes 10 to 20 minutes 61,62 Optimal application can be challenging, however, and a learning curve should be expected The target site should be deflated and free of blood and active air leakage The sealant should be applied as a thin layer without air bubbles The primer and sealant are applied to the target site and cm of surrounding tissue In an experimental study, 10 dogs underwent thoracotomy and amputation of the lung apex.63 Dogs were then randomized to treatment with FocalSeal or no further treatment and were observed for 24 hours after surgery All control animals had persistent air leaks, whereas none of the animals in the FocalSeal group had detectable air leaks immediately after surgery Only of dogs in the FocalSeal group developed an air leak 17 hours after surgery Macchiarini and colleagues performed left upper lobectomy on 15 pigs, then randomized them to have the bronchial stumps either stapled (n = 5), sealed with FocalSeal (n = 5), or stapled and sealed with FocalSeal (n = 5).61 The divided fissure was stapled and sealed with FocalSeal in all animals There were no air leaks in any of the pigs postoperatively Histopathologic findings after the pigs were euthanized weeks postoperatively showed similar healing and inflammation characteristics among the groups.61 This latter group also conducted a prospective, randomized clinical study in which pulmonary parenchymal surgical sites were treated with conventional closure plus FocalSeal (n = 15) or conventional closure alone (n = 11).61 None of the patients in the FocalSeal group had detectable air leaks intraoperatively, whereas only 18% of the control group was free of air leaks prior to chest closure (p = 001) In the FocalSeal group, only 23% had an air leak from the time of surgery until chest tube removal versus 91% of the control group (p = 001) However, there was no significant difference between the groups in the time to chest tube removal or the length of the hospital stay.61 Porte and colleagues randomized 124 patients undergoing lobectomies to treatment with conventional closure alone (n = 62) or conventional closure plus treatment of parenchymal surgical sites with Advaseal (Johnson & Johnson) (n = 62).64 In this study all patients had chest tubes removed after days, regardless of the presence of air leaks Four patients in the sealant group developed empyema and drained “infected surgical lung sealant.” Patients in the sealant group had fewer perioperative air leaks and shorter time from surgery until the last detectable air leak than did those in the control group; FIGURE 3-7 FocalSeal-L pulmonary sealant system contents include a xenon light source and light wand and application devices for the primer and sealant (Courtesy of Genzyme Biosurgery) ... mL/h 10 ? ?15 µg q10? ?15 prn 5–7 µg q10? ?15 prn 3–6 mg q6? ?12 h prn 0.2–0.3 mg q10? ?15 prn 0.8? ?1. 5 mg q4–6h prn 0 .15 –0.3 mg q10? ?15 prn 1? ??2 mL q10? ?15 prn 6–8 mL/h 1? ??2 mL q10? ?15 prn 6–8 mL/h 1? ??2 mL q10? ?15 ... Surg 19 90;4:407? ?11 11 2 Richardson J, Sabanathan S Thoracic paravertebral analgesia Acta Anaesthesiol Scand 19 95;39 :10 05? ?15 11 3 Leach A “Old ideas, new applications.” Br J Anaesth 19 98; 81: 113 –5 11 4... fibrinogen, human thrombin, bovine aprotinin, CaCl Human fibrinogen, human thrombin, bovine aprotinin, CaCl Bovine serum albumin, glutaraldehyde Bovine thrombin, collagen-gelatin matrix Two-component