Athoracotomy is particularly painful, and good pain

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1 Efficacy of Methods of Intercostal Nerve Blockade for Pain Relief After Thoracotomy Frank C. Detterbeck, MD Division of Cardiothoracic Surgery, University of North Carolina, Chapel Hill, North Carolina Intercostal nerve blockade for postthoracotomy pain relief can be accomplished by continuous infusion of local anesthetics through a catheter in the subpleural space or through an interpleural catheter, by cryoanalgesia, and by a direct intercostal nerve block. A systematic review of randomized studies indicates that an extrapleural infusion is at least as effective as an epidural and significantly better than narcotics alone. The other techniques of intercostal blockade do not offer an advantage over narcotics alone. (Ann Thorac Surg 2005;80:1550 9) 2005 by The Society of Thoracic Surgeons Athoracotomy is particularly painful, and good pain control is crucial to maximize the ability to cough and breathe. The most common methods of postoperative pain management are systemic narcotics and epidural administration of local anesthetic agents or narcotics [1]. Techniques involving intercostal nerve blockade are used less often, although this may be unjustified. This article is a systematic review of intercostal nerve blockade after thoracotomy. It is restricted to efficacy data from randomized studies involving any techniques of intercostal nerve blockade. The simplest method of intercostal nerve blockade is injection of local anesthetics in multiple intercostal nerves before closure of a thoracotomy incision. A longerlasting method involves cryotherapy of intercostal nerves. Continuous infusion or serial administration of local anesthetics through an indwelling catheter for several days can be performed through an interpleural catheter (by anesthetic diffusion across the pleura and inner chest wall to the intercostal nerves) or through a catheter placed in a subpleural (extrapleural) pocket (closer to the nerves). Each of these methods is discussed separately. Material and Methods A MEDLINE English-language literature search was performed using the key words thoracotomy, pain, postoperative, analgesia, intercostal nerve, epidural, subpleural, extrapleural, interpleural and intrapleural, cryoanalgesia, and randomized. The references of included studies, selected textbooks, practice guidelines, systematic reviews, and meta-analyses were also reviewed to identify all relevant studies. Predetermined inclusion criteria were a randomized study of patients undergoing thoracotomy in which a method of intercostal nerve blockade was compared with Address reprint requests to Dr Detterbeck, Division of Cardiothoracic Surgery, University of North Carolina, CB #7065, Medical School Wing C Room 354, Chapel Hill, NC ; fdetter@ med.unc.edu. either systemic narcotics or an epidural analgesia technique. Randomized studies involving a different control group are included in the discussion as appropriate. Duplicate publications were excluded, ie, earlier publications of patients included in a subsequent larger report. However, studies were included if it was unclear whether the same patients were reported elsewhere. Evidence tables were constructed according to the criteria listed in the legend of each table. The relative paucity of studies, the variability in the durations of patient assessments, and the subjective nature and variability in pain assessment prevent a formal meta-analysis of these data. Results Extrapleural Infusion of Local Anesthetics TECHNIQUE. A portion of the parietal pleura can be easily lifted away from the inner chest wall during a thoracotomy to create an extrapleural pocket. A catheter is introduced percutaneously into this pocket under direct vision, often with a Tuohy needle (typically used for epidural catheter placement). The overlying pleura is sutured closed at the thoracotomy incision site. Some authors have used a curved vascular clamp to simultaneously create the tunnel and pull the catheter along [2], while others use flexible bronchoscopy biopsy forceps through a small nick in the pleura to pull the catheter into the subpleural pocket [3]. Percutaneous catheter placement into this space without intraoperative visualization has also been described [4, 5], albeit with technical failure in 10% to 30% and complications in 10% (hypotension, vascular or pleural puncture) [4, 5]. Infusion of local anesthetics through the catheter fills the extrapleural pocket, and diffuses across the endothoracic fascia and internal intercostal muscles to cause intercostal nerve blockade. Postoperative imaging stud- Dr Detterbeck discloses that he has a financial relationship with I-Flow, Corp by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg REVIEW DETTERBECK 2005;80: INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 1551 ies have shown that the fluid remains in the extrapleural space without leakage into the pleural space [6, 7]. Some authors place the catheter when convenient lateral to the spine [8 10], while others emphasize placement close to the heads of the ribs in the paravertebral space [6, 7, 11] because there the intercostal nerves are not enveloped by a fascial sheath and the sympathetic ganglia, posterior intercostal rami, and nerve branches to the costovertebral joints are also blocked [7, 12]. Although many types of catheters are used, a small catheter with multiple side holes, such as an epiduraltype catheter or an On-Q soaker catheter (I-Flow Corporation, Lake Forest, CA), is most appealing. Most authors have placed a catheter with side holes across multiple intercostal levels [10, 11], while others have placed one catheter above and one below the incision [8], and others have used multiple intercostal catheters [13]. The vast majority of authors use 0.5% bupivacaine as a local anesthetic [3, 9, 11, 14 18], although some use 0.25% bupivacaine [6, 10, 19 22], 1% lidocaine [9, 23], or 1% lignocaine [6]. The rate of infusion is generally 5 to 7 ml/h for an average-sized adult (0.1 ml kg 1 h 1 ) [3, 6, 9, 11, 14 16, 18, 19, 21 23]. Analgesia to pinprick (approximately 5 dermatomes unilaterally) is similar to a thoracic epidural (bilaterally) [19]. EFFICACY. Randomized studies of an extrapleural catheter in patients undergoing thoracotomy are summarized in Table 1. All but two of the studies involving narcotics are double-blind and placebo-controlled. Overall, the data demonstrate that extrapleural analgesia is superior to systemic narcotics. All of the studies have found that pain relief was better, although the difference was not statistically significant in two of seven studies. Moreover, better pain relief was achieved despite a decreased use of supplemental narcotics in most studies. The incidence of pulmonary complications was generally lower in the extrapleural group. There was also better preservation of the forced expiratory volume in 1 second (FEV 1 ) in most studies (although one found a trend to worse results). Randomized studies comparing an extrapleural technique with epidural analgesia suggest that outcomes are at least as good, if not better, using an extrapleural approach. Pain relief is somewhat better and narcotic usage somewhat less with an extrapleural catheter, but the differences are not consistent and often not statistically significant. Extrapleural analgesia may preserve FEV 1 better, but the effect on pulmonary complications is unclear. One study compared extrapleural with interpleural administration of local anesthetics [14]. No difference in pain was noted, although pulmonary complications were decreased and FEV 1 better preserved by the extrapleural approach. The lack of a difference in pain control is surprising, given how consistently better extrapleural analgesia is compared with systemic narcotics, which yield similar relief compared with interpleural analgesia (see next section). The poor FEV 1 results with interpleural bupivacaine in this study [14] may be caused by bupivacaine pooling above the diaphragm, causing diaphragmatic impairment. Randomized studies comparing extrapleural infusions of bupivacaine and lidocaine or lignocaine found no difference in pain relief, need for supplemental narcotics, or pulmonary function [6, 9]. These authors argue that lidocaine may be better than bupivacaine because of a larger therapeutic window, a lower risk of cardiac toxicity, and the notion that a constant infusion thwarts any advantage of a longer-acting agent. However, this argument is countered by the extensive experience and minimal toxicity with bupivacaine. TOXICITY. Extrapleural infusion of bupivacaine has been very well tolerated. Local complications were seen in 0.6% of patients (2 of 311) in studies that specifically reported complications (1 patient each with transient hypotension and transient Horner s syndrome) [3, 6, 9 11, 15 17, 22, 24 26]. Systemic bupivacaine toxicity (confusion) was noted in 0.8% of patients (3 of 383) [3, 6, 8 11, 14 20, 22, 24, 26]. Two additional patients experienced confusion thought to be unrelated because their plasma bupivacaine levels were well below the toxic range [19]. One patient experienced rib osteomyelitis as a result of the catheter [21]. No other complications have been reported. Toxicity to other local anesthetics has not been reported. More side effects have occurred in patients receiving an epidural in studies comparing extrapleural bupivacaine with epidural techniques [18, 22, 26]. Average plasma bupivacaine levels during continuous infusion for several days are 3 to 4 g/ml (range, 2.1 to 4.92 g/ml) in studies that have measured this [8, 16, 19, 26, 29, 30], which is close to the commonly accepted threshold of 5 g/ml for central nervous system toxicity [30]. Maximal levels of 7.48 g/ml [29] and g/ml [16] have been reported, but these patients did not experience toxicity. The explanation may be that the vast majority of plasma bupivacaine during an infusion is bound to serum proteins and is thereby rendered biologically inactive [30]. Furthermore, studies attempting to define a toxic plasma level have been unable to do so, and the incidence of toxicity appears to be related to the rapidity of administration [31]. Interpleural Administration of Local Anesthetics TECHNIQUE. Interpleural administration of local anesthetics is accomplished by introducing a small catheter percutaneously into the pleural space before thoracotomy closure. An epidural-type catheter with multiple side holes is generally used, and positioned posteriorly in the paravertebral gutter, spanning several intercostal spaces above and below the incision. Usually intermittent doses of bupivacaine are given every 4 [32 37],6[38], or 8 hours [39, 40], but some authors use a constant infusion [14, 41]. The dose of bupivacaine is not consistent, but the most common volume is 20 ml, and the most common concentration is 0.5% (with epinephrine in about half of the studies). In approximately half of the studies the chest tubes were clamped for 5 to 30 minutes after the dose was given [33 35, 37, 38, 40, 42]; in others,

3 Table 1. Studies of the Value of Extrapleural Local Anesthetics a Study n Standard Experimental VAS Pain Narcotic Use FEV 1 Complications Pulmonary Best Arm p Value Best Arm p Value Best Arm p Value Best Arm p Value Eng and Sabanathan [25] 80 Narc B, infus ExPl 0.01 ExPl 0.01 ExPl 0.01 ExPl 0.01 Sabanathan et al. [24] 56 Narc B, infus ExPl 0.01 ExPl 0.01 ExPl 0.01 ExPl? Deneuville et al. [17] 52 Narc B, infus (ExPl) b NS No Diff NS No Diff NS ExPl 0.05 Bilgin et al. [3] 50 Narc B, q4 ExPl 0.05 ExPl 0.05 ExPl? Berrisford et al. [27] 46 Narc B, infus ExPl 0.01 ExPl 0.01 ExPl 0.01 ExPl 0.05 Perttunen et al. [19] c,d 30 Narc e B, infus (ExPl) b NS (ExPl) b NS (Narc) b NS Chan et al. [8] f 20 Narc B, q6 ExPl 0.05 ExPl 0.05 ExPl Mozell et al. [15] 16 Narc B, infus ExPl 0.01 ExPl 0.01 ExPl 0.01 No Diff NS de la Rocha and Chambers [28] c,g 10 Narc B, q (ExPl) b NS Richardson et al [18] c 100 Epi B, infus ExPl 0.02 ExPl ExPl h 0.05 ExPl Bimston et al. [26] c 47 Epi i B/F, infus (Epi) b NS j No Diff NS No Diff NS Debreceni et al. [21] f 47 Epi B, infus Epi 0.05 k (Epi) b NS No Diff NS Kaiser et al. [16] c 30 Epi i B, infus ExPl 0.05 ExPl 0.05 ExPl.05 ExPl? Perttunen et al. [19] c,d 30 Epi B, infus (ExPl) b NS (ExPl) b NS (Epi) b NS Richardson et al [20] f 20 Epi l B, infus (ExPl) b NS (ExPl) b NS... NS Matthews and Govenden [22] c,f 19 Epi B, infus No Diff NS a Values for VAS pain scores, narcotic use, and FEV 1 represent a composite of results during 3 to 5 days except as indicated; the incidence of pulmonary complications is calculated for the duration of the hospital stay. All epidural techniques involved a thoracic epidural with infusion of bupivacaine except as noted otherwise. b Trends that are not statistically significant are indicated in parentheses. c Not blinded. d Data collection for 2 days only. e A direct intercostal nerve block was also performed intraoperatively in all patients. f Data collection for 24 hours only. g Four catheters used to block four intercostal nerves. h Peak expiratory flow rate. i Bupivacaine and fentanyl. j Significant difference for the first 32 hours. k Not significant after 12 hours. l Lumbar epidural with morphine infusion. Inclusion criteria: randomized studies of postoperative analgesia in patients undergoing thoracotomy, involving an extrapleural technique compared with either systemic narcotics or an epidural technique.? value not calculated; B bupivacaine; B/F bupivacaine and fentanyl; Epi epidural; ExPl extrapleural; FEV 1 forced expiratory volume in 1 second; Infus continuous infusion; Narc narcotic; No Diff no discernible difference; NS not statistically significant; p level of statistical significance; q4 every 4 hours; q6 every 6 hours; VAS Pain Visual Analog Scale Pain assessment REVIEW DETTERBECK Ann Thorac Surg INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 2005;80:1550 9

4 Ann Thorac Surg REVIEW DETTERBECK 2005;80: INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 1553 gravity drainage [39] or suction was maintained throughout [14, 32, 36, 41, 43]. Management of the chest tubes may be important because a large portion (about 30%) of the administered dose drains from the tubes within 15 minutes [33, 36, 43, 44]. One randomized study suggested that epinephrine was not needed, and that two catheters may be better than one [36]. EFFICACY. Randomized studies (mostly double-blind, placebo-controlled) of interpleural local anesthetics after thoracotomy suggest that the benefit of this approach is marginal, at best (Table 2). Most studies have found no difference in patients perception of pain or need for narcotics, although two studies found both of these outcomes to be significantly better using an interpleural approach compared with narcotics alone. The limited available data regarding pulmonary function tests or respiratory complications do not suggest that interpleural local anesthetics offer a benefit. The few studies comparing an interpleural with an epidural approach have either found no difference in pain control or found a benefit to an epidural technique. In general, blockage of approximately four dermatomes has been achieved in the one study that assessed this [36]. TOXICITY. No complications owing to interpleural catheter placement have been reported. Confusion thought to be related to systemic bupivacaine toxicity was reported in 5% (7 of 147) of patients overall [14, 32, 35, 37, 41 43], although this complication occurred primarily in one study using a constant infusion (5 of 23 patients) [14]. Among studies using intermittent dosing, bupivacaine toxicity occurred in 2.1% (2 of 94) [32, 35, 37, 42]. Other complications have included upper extremity tingling and urinary retention [42, 43]. Average plasma bupivacaine levels have generally been approximately 1 g/ml (0.32 to 2.29 g/ml) [33, 39, 42, 43, 45], but there is wide individual variation among patients [35]. The amount of bupivacaine lost in the chest tubes does not seen to correlate with either the plasma levels or the degree of pain relief [36, 37]. The variability in efficacy and toxicity of interpleural analgesia may be related to pleural permeability, inflammation, adhesions, and dilution with blood or effusion. Cryoanalgesia TECHNIQUE. Cryoanalgesia involves freezing intercostal nerves to 60 C for 30 to 45 seconds, which causes damage to the myelin sheath, thereby interrupting nerve conduction. The nerve axon, however, is unharmed, so that functional recovery of the nerve occurs once the myelin sheath has regenerated [46, 47]. This process generally takes about 1 to 3 months in the case of intercostal nerves [47, 48]. Usually the intercostal nerves are isolated and the cryoprobe is applied directly, although some authors have applied the probe over the intact pleura, provided the pleura is thin [48]. In some studies the nerve has been frozen twice, in others a single application of a cryoprobe was used. Usually the nerve along the intercostal incision and at least one nerve above and one below are frozen (range, three to eight nerves). This technique was practiced fairly commonly during the 1980s, especially in several European centers, but fell out of favor around This corresponded with more widespread availability of epidural anesthesia, as well as concerns about the efficacy and the potential for neuralgia. EFFICACY. Randomized studies of cryoanalgesia for postthoracotomy pain relief (Table 3) compared with narcotics suggest marginally better pain relief and a trend to less supplemental narcotics with cryotherapy, although many studies have found no difference. However, no study suggested that cryoanalgesia resulted in worse pain control. Three studies found no difference in the postoperative FEV 1 [38, 49, 50], although one study noted a benefit to cryotherapy versus narcotics [51], and two found a trend to a benefit [47, 52]. The studies addressing pulmonary complications suggested that cryoanalgesia was beneficial [47, 53]. Most of these studies were conducted in a blinded fashion. Comparison of cryoanalgesia with epidural analgesia suggests worse pain relief and more supplemental narcotics with cryoanalgesia, although the data are limited. TOXICITY. Concern has been raised about the development of neuralgia after cryoanalgesia of intercostal nerves, generally occurring after about 6 weeks, and lasting for 2 to 4 weeks [38, 47, 49, 54, 55, 57]. The incidence is reported to be 20% to 30% in several studies [38, 49, 54, 57, 58], although other authors have not encountered this problem in a large cohort of patients (71 patients) who were monitored for 3 months [53]. In addition, the incidence of postthoracotomy pain syndrome which may or may not be the same as neuralgia after cryoanalgesia was found to be less after cryoanalgesia than after epidural, narcotic, or interpleural management of postthoracotomy pain in one study [38]. Other complications of cryoanalgesia have not been reported. Direct Intercostal Nerve Block TECHNIQUE. Intercostal nerves can be injected percutaneously from outside the chest or under direct vision from inside the chest before thoracotomy closure. The blocks are administered just below a rib in the region of the intercostal bundle, being careful not to inject the dose intravascularly. In most studies 2 ml of 0.5% bupivacaine per intercostal nerve is used, although some have injected larger volumes [59 61] or used 0.25% bupivacaine [62]. In most studies bupivacaine without epinephrine has been used. Some authors have administered the first block percutaneously before the incision [63]. Most authors have administered the intercostal block only once, although some have repeated the blocks during the course of 24 hours [63]. EFFICACY. Intercostal nerve block before thoracotomy closure has generally provided better pain relief than narcotics alone, although a reduction in supplemental medication is less clear (Table 4). Interestingly, better pain relief occurred even in studies that assessed pain more than 3 to 5 days, even though the intercostal block was not repeated [60, 64]. Segmental analgesia to pinprick extended to 18 hours in one study after 0.5% bupivacaine

5 Table 2. Studies of the Value of Interpleural Local Anesthetics a Study n Standard Experimental VAS Pain Narcotic Use FEV 1 Complications Pulmonary Best Arm p Value Best Arm p Value Best Arm p Value Best Arm p Value Silomon et al. [37] b 83 Narc B q4 No Diff NS No Diff NS No Diff NS No Diff NS Mann et al. [32] 33 Narc B q4 InPl 0.05 No Diff NS InPl Miguel and Hubbell [38] c 21 Narc B q6 No Diff NS (InPl) d NS No Diff NS Francois et al. [35] 20 Narc L q4 No Diff e NS e (Narc) d NS Francois et al. [35] 20 Narc B q4 No Diff e NS e InPl Bachmann-Mennenga 20 Narc B infus (Narc) d... NoDiff NS et al. [45] e,f Tartiere et al. [40] 20 Narc B/E q8 InPl 0.05 InPl 0.05 (Narc) d NS Scheinin et al. [33] b,c 20 Narc g Bq4 g No Diff NS (InPl) d NS Schneider et al. [34] 19 Narc B q4 No Diff NS No Diff NS No Diff NS Raffin et al. [44] b 16 Narc L infus No Diff NS (InPl) d NS (InPl) d NS No Diff NS Symreng et al. [39] h 15 Narc B q8 2 No Diff NS i No Diff NS i InPl Brockmeier et al. [41] h 32 Epi B infus No Diff NS No Diff NS Miguel and Hubbell [38] c 21 Epi j B q6 Epi (InPl) d NS Bachmann-Mennenga et al. [45] c,f 20 Epi B infus (Epi) d... Epi a Values for VAS pain scores, narcotic use, and FEV 1 represent a composite of results during 3 to 5 days except as indicated; the incidence of pulmonary complications is calculated for the duration of the hospital stay. All epidural techniques involved a thoracic epidural with infusion of bupivacaine except as noted otherwise. b Data collection for 2 days only. c Not blinded. d Trends that are not statistically significant are indicated in parentheses. e Study involved both a thoracotomy and laparotomy; pain was significantly better in the interpleural group when only the thoracotomy incision was analyzed. f Duration of data collection not specified. g A direct intercostal block was performed intraoperatively in all patients. h Data collection for 24 hours only. i No difference overall, but pain and narcotic use were reduced for several hours after interpleural bupivacaine injection. j Lumbar epidural with lidocaine infusion. Inclusion criteria: randomized studies of postoperative analgesia in patients undergoing thoracotomy, involving an interpleural technique compared with either systemic narcotics or an epidural technique. B bupivacaine; B/E bupivacaine and epinephrine; Epi epidural; FEV 1 forced expiratory volume in 1 second; Infus continuous infusion; InPl interpleural; L lidocaine; Narc narcotic; No Diff no discernible difference; NS not statistically significant; p level of statistical significance; q4 every 4 hours; q6 every 6 hours; q8 every 8 hours; VAS Pain Visual Analog Scale Pain assessment; 2 twice REVIEW DETTERBECK Ann Thorac Surg INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 2005;80:1550 9

6 Table 3. Studies of the Value of Cryoanalgesia a Study n Standard Experimental VAS Pain Narcotic Use FEV 1 Complications Pulmonary Best Arm p Value Best Arm p Value Best Arm p Value Best Arm p Value Moorjani et al. [47] b 200 Narc 4 ICN (Cryo) c NS Cryo 0.05 (Cryo) c NS (Cryo) c... Roberts et al. [53] 144 Narc d 8 ICN d Cryo 0.05 Cryo Cryo 0.05 Brichon et al. [52] b 74 Narc 5 ICN (Cryo) e NS (Cryo) e NS (Cryo) c NS Müller et al. [49] 63 Narc 4 ICN No Diff NS No Diff NS No Diff e NS Keenan et al. [50] f,g 60 Narc 5 ICN Cryo 0.01 (Cryo) c NS No Diff e NS Rooney et al. [51] 50 Narc 3 ICN Cryo Orr et al. [56] b,g 30 Narc d 5 ICN d NoDiff NS NoDiff NS Miguel and Hubbell [38] b 25 Narc 3 ICN (Cryo) c NS (Cryo) c NS No Diff NS Brichon et al. [52] b 87 Epi h 5 ICN Epi 0.05 Epi 0.05 No Diff NS Gough et al. [55] b 68 Epi i 6 ICN (Epi) c NS Epi No Diff NS Roxburgh et al. [54] 53 Epi j 5ICN NoDiff NS NoDiff NS Miguel and Hubbell [38] b 24 Epi k 3 ICN No Diff NS (Cryo) c NS a Values for VAS pain scores, narcotic use, and FEV 1 represent a composite of results during 3 to 5 days except as indicated; the incidence of pulmonary complications is calculated for the duration of the hospital stay. All epidural techniques involved a thoracic epidural with infusion of bupivacaine except as noted otherwise. b Not blinded. c Trends that are not statistically significant are indicated in parentheses. d A direct intercostal block was performed intraoperatively in all patients. e Peak expiratory flow rate. f Factorial design with and without indomethacin. g Data collection for 2 days only. h Bupivacaine and fentanyl infusion. i Fentanyl infusion. j Lumbar epidural with morphine infusion. k Lumbar epidural with lidocaine infusion. Inclusion criteria: randomized studies of postoperative analgesia in patients undergoing thoracotomy, involving a cryoanalgesia compared with either systemic narcotics or an epidural technique. Cryo cryoanalgesia; Epi epidural; ExPl extrapleural; FEV 1 forced expiratory volume in 1 second; ICN intercostal nerves; Narc narcotic; No Diff no discernible difference; NS not statistically significant; p level of statistical significance; VAS Pain Visual Analog Scale Pain assessment. Ann Thorac Surg REVIEW DETTERBECK 2005;80: INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 1555

7 Table 4. Studies of the Value of Direct Intercostal Nerve Injection a Study n Standard Experimental VAS Pain Narcotic Use FEV 1 Complications Pulmonary Best Arm p Value Best Arm p Value Best Arm p Value Best Arm p Value Galway et al. [59] b,c 92 Narc B/E 1 ICB 0.05 No Diff NS No Diff d NS Galway et al. [59] b,c 92 Narc L/E 1 ICB 0.05 No Diff NS No Diff d NS Roviaro et al. [65] c 73 Narc Ph (ICB) e NS Delilkan et al. [66] c 40 Narc B/E 1 ICB 0.01 ICB ICB 0.01 (ICB) e NS Holley et al. [67] c 40 Narc B/E NoDiff NS NoDiff NS Faust and Nauss [68] b,f 34 Narc B/E (ICB) e NS (ICB) e? Asantila et al. [63] b,g 20 Narc B 3 No Diff NS (ICB) e NS (ICB) e NS Toledo-Pereyra and 20 Narc B 1 ICB? ICB 0.05 ICB 0.05 No Diff NS DeMeester [64] b Bachmann-Mennenga 20 Narc B 1 (ICB) e... ICB et al. [45] b,h Liu et al. [69] 20 Narc i B 1 No Diff NS (ICB) e NS No Diff. NS Kaplan et al. [60] 18 Narc B 1 ICB No Diff NS ICB No Diff NS de la Rocha and 10 Narc B/E (ICB) e NS Chambers [28] b Takamori et al. [62] b 40 Epi j B 1 ICB No Diff NS Wurnig et al. [61] b 30 Epi k B 1 (Epi) e NS (Epi) e? Perttunen et al. [19] b,g 30 Epi B 1 (ICB) e NS No Diff NS No Diff NS Asantila et al. [63] b,g 20 Epi B 3 No Diff NS Epi 0.01 No Diff NS Bachmann-Mennenga et al. [45] b,h 20 Epi B 1 No Diff... (ICB) e NS a Values for VAS pain scores, narcotic use, and FEV 1 represent a composite of results during 3 to 5 days except as indicated; the incidence of pulmonary complications is calculated for the duration of the hospital stay. All epidural techniques involved a thoracic epidural with infusion of bupivacaine except as noted otherwise. b Not blinded. c Data collection for 24 hours only. d Peak expiratory flow rate. e Trends that are not statistically significant are indicated in parentheses. f Data collection for 1 hour only. g Data collection for 2 days only. h Duration of data collection not specified. i Single injection of lumbar intrathecal morphine in all patients. j Thoracic epidural with mepivacaine infusion. k Thoracic epidural with bupivacaine and fentanyl infusion. Inclusion criteria: randomized studies of postoperative analgesia in patients undergoing thoracotomy, involving a direct intercostal nerve injection technique compared with either systemic narcotics or an epidural technique.? value not calculated; B bupivacaine; B/E bupivacaine and epinephrine; Epi epidural; FEV 1 forced expiratory volume in 1 second; ICB intercostal block; InPl interpleural; L/E lidocaine and epinephrine; Narc narcotic; No Diff no discernible difference; NS not statistically significant; p level of statistical significance; Ph phenol; VAS Pain Visual Analog Scale Pain assessment; 1 once; 3 three times REVIEW DETTERBECK Ann Thorac Surg INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 2005;80:1550 9

8 Ann Thorac Surg REVIEW DETTERBECK 2005;80: INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 1557 without epinephrine [19]. Pulmonary function also appears to be better preserved, even several days later, but an effect on pulmonary complications is unclear. Almost all of these studies were not blinded. In studies comparing intercostal nerve block with epidural analgesia, neither technique is clearly superior. Pain control may be slightly better with intercostal blocks, although narcotic use may be less with an epidural. There is no apparent difference in pulmonary function testing. Most studies were small, so that small differences may be missed. Nevertheless, the lack of consistent trends among these studies calls into question the widely presumed superiority of the epidural approach [1]. TOXICITY. Intercostal nerve blocks are associated with minimal side effects. A study of almost 11,000 patients receiving percutaneous intercostal nerve blocks found no episodes of systemic toxicity to local anesthetics [70]. The incidence of pneumothorax was 0.07%, although this is not germane to intraoperative administration of the block [70]. Plasma bupivacaine levels have been low after intercostal nerve blocks (0.19 to 1.46 g/ml with a peak at 10 minutes) [19]. Even a continuous infusion for more than 5 days has been found to be safe, with local anesthetic levels that are below toxic levels [71]. Comment Although intercostal nerve blockade (by any method) for treatment of postthoracotomy pain is not currently widely practiced, the data presented here suggest that perhaps this should be reconsidered. The most common method of postthoracotomy analgesia, a thoracic epidural infusion [1], is associated with frequent side effects, including urinary retention (42%), nausea (22%), itching (22%), and hypotension as a result of decreased sympathetic tone (3%) [72, 73]. A more rare effect is respiratory depression (0.07%), necessitating management of patients in a highly monitored setting, or the involvement of a specialized pain service [72, 73]. Furthermore, the epidural placement lengthens the operative time and is associated with occasional technical failure or dislodgement (8%) [72]. The most common alternative analgesic method, systemic narcotics, also has frequent side effects, including constipation, nausea, somnolence, and respiratory depression. Nevertheless, both epidural analgesia and systemic narcotics are used in the vast majority of patients undergoing thoracotomy because of the importance of providing postoperative pain relief. A continuous infusion of local anesthetics through an extrapleural catheter results in more effective pain relief than systemic narcotics. In fact, the pain relief afforded by the extrapleural technique appears to be at least as good as an epidural approach. Catheter placement at the time of thoracotomy or thoracoscopy can be accomplished quickly and reliably. Because the extrapleural route results in only a unilateral blockade, the incidence of side effects such as hypotension and urinary retention is greatly diminished. There is no risk of respiratory depression and no need for intensive monitoring or specialized services for management. Although an extrapleural approach does not always eliminate the need for systemic narcotics, the amount needed is reduced. The value of other techniques of intercostal nerve blockade is less clear. Interpleural local anesthetic results in inconsistent pain relief. Although catheter placement is straightforward, the risk of side effects appears to be slightly higher than with an extrapleural route. As a result, this technique is currently used only rarely. Cryoanalgesia appears to be of some benefit relative to systemic narcotics, but the results are less consistent compared with an extrapleural catheter, and appear to be worse than with an epidural approach. Furthermore, cryoanalgesia carries a significant risk of postoperative hyperesthesia. Direct intercostal nerve blockade appears to provide a benefit compared with narcotics alone in several older studies, particularly during the first day, but the short duration of action makes this approach less appealing. A more detailed understanding of the pathophysiology of postoperative pain has evolved [74]. Tissue injury causes peripheral sensitization through the release of mediators, so that there is both an exaggerated response of the high-threshold A and C fibers that are responsible for transmission of true noxious stimuli. This results in exaggerated responsiveness of nerves in the affected area (primary hyperalgesia), as well as an exaggerated response in surrounding uninjured tissue (secondary hyperalgesia) [74]. In addition, noxious stimuli (pain) elicit changes in the dorsal horn neurons of the spinal cord known as central sensitization. This has the effect that stimuli from low-threshold A fibers, which are normally perceived as relatively innocuous, are now perceived as pain (pathologic pain) [74]. These physiologic changes have been demonstrated in humans using a variety of experimental approaches. In addition, there is evidence from several avenues of investigation that these early changes precipitate the development of chronic pain [57, 74, 75]. The more sophisticated understanding of the physiology of pain has led to the recommendation for a multifaceted approach to postoperative analgesia to prevent the sensitization that amplifies the sensation of pain. Nonsteroidal antiinflammatory agents decrease peripheral as well as central sensitization [74, 76]. Preoperative narcotics decrease central sensitization. However, the major factor in decreasing sensitization seems to be blocking the neural transmission of nociceptive stimuli that result from the incision, something that systemic narcotics alone cannot achieve. An intercostal block leads to a more effective block of nociceptive stimuli than an epidural approach [74]. Highly effective postthoracotomy pain relief has been demonstrated using such a multifaceted approach [77], and the intercostal block appears to be the most important component [77]. Whether analgesic agents are given preoperatively or postoperatively does not seem to be important [78]. Better early pain relief has been associated with a lower incidence of

9 1558 REVIEW DETTERBECK Ann Thorac Surg INTERCOSTAL NERVE BLOCK FOR PAIN RELIEF 2005;80: chronic postthoracotomy pain [75, 79], consistent with the theory of the pathophysiology of chronic pain. In conclusion, continuous intercostal nerve blockade after thoracotomy using an extrapleural catheter results quite consistently in better pain relief and preservation of pulmonary function than systemic narcotics, and appears to be at least as good as an epidural approach. The ease of the extrapleural approach and the low incidence of complications suggest this technique should be used more frequently. Other methods of intercostal nerve blockade appear to be less effective, although direct intercostal nerve injection may decrease pain in the immediate postoperative period. The use of a multifaceted approach to postthoracotomy analgesia that includes intercostal nerve blockade may be beneficial in the immediate postoperative period as well as reduce the incidence of chronic pain. 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