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Table of Contents
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 15  |  Issue : 1  |  Page : 32-38
The effect of low-dose intravenous ketamine on continuous intercostal analgesia following thoracotomy


Department of Anaesthesia and Surgical Intensive Care, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon

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Date of Submission24-Jun-2011
Date of Acceptance20-Sep-2011
Date of Web Publication5-Jan-2012
 

   Abstract 

Ketamine, a noncompetitive N-methyl-d-aspartate antagonist, provides analgesia and prevents chronic pain following thoracotomy. The study was aimed to assess the effect of intravenous low-dose ketamine on continuous intercostal nerve block analgesia following thoracotomy. The study was a prospective, randomized, double-blinded, and placebo-controlled clinical study, performed in a single university hospital. Sixty patients, undergoing elective lobectomy through an open posterolateral thoracotomy, were included. For postoperative pain, all patients received a continuous intercostal nerve block with bupivacaine plus intravenous paracetamol and ketoprofen. In addition, patients were randomized to have intravenous ketamine (0.1 mg/kg as a preincisional bolus followed by a continuous infusion of 0.05 mg/kg/h) in group 1 or intravenous placebo in group 2. Patients reporting a visual analog scale pain score at rest ≥40 mm received intravenous morphine sulfate as rescue analgesia. The following parameters were assessed every 6 hours for 3 postoperative days: Visual analog scale pain scores at rest and during coughing, requirement of rescue analgesia with morphine, Ramsay sedation scores and psychomimetic adverse effects. Both the groups were statistically comparable regarding visual analog scale pain scores at rest (P=0.75) and during coughing (P=0.70), number of morphine deliveries (P=0.17), cumulative dose of rescue morphine (P=0.2), sedation scores (P=0.4), and psychomimetic adverse effects (P=0.09). Intravenous low-dose ketamine, when combined with continuous intercostal nerve block, did not decrease acute pain scores and supplemental morphine consumption following thoracotomy.

Keywords: Intercostal nerve block, ketamine, postoperative pain, thoracotomy

How to cite this article:
Yazigi A, Abou-Zeid H, Srouji T, Madi-Jebara S, Haddad F, Jabbour K. The effect of low-dose intravenous ketamine on continuous intercostal analgesia following thoracotomy. Ann Card Anaesth 2012;15:32-8

How to cite this URL:
Yazigi A, Abou-Zeid H, Srouji T, Madi-Jebara S, Haddad F, Jabbour K. The effect of low-dose intravenous ketamine on continuous intercostal analgesia following thoracotomy. Ann Card Anaesth [serial online] 2012 [cited 2019 Jul 21];15:32-8. Available from: http://www.annals.in/text.asp?2012/15/1/32/91479



   Introduction Top


Inadequate analgesia following thoracotomy is associated with severe postoperative patient discomfort and alteration of ventilatory mechanics. Impaired ability to breathe deeply, ineffective cough and poor clearance of secretions may result in atelectasis, pneumonia, and increased postoperative morbidity. [1] Due to the multiplicity of nociceptive inputs from the lung, chest wall, diaphragm, and chest tubes, combined regional and systemic analgesia is used for postoperative pain control. Continuous intercostal nerve block is among the regional analgesia techniques used to control pain following thoracic surgery. [2],[3],[4],[5] This block is provided by continuous infusion of local anesthetics through an indwelling catheter placed under direct vision in an extra pleural pocket at the level of the surgical incision. In most of the reported studies, continuous intercostal nerve block is supplemented by systemic analgesic, such as opiate, nonsteroidal anti-inflammatory agents, and paracetamol. [2],[3],[4],[5],[6]

Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, produces central antinociception by reducing the sensitization of C fibers at the spinal and supra spinal levels. It also enhances analgesia because of its local anesthetic properties and its interaction with spinal opioid receptors. Several authors reported the use of ketamine to provide analgesia and to prevent chronic pain following thoracotomy. [7],[8],[9] Low-dose intravenous ketamine enhanced epidural analgesia [10] and morphine patient-controlled analgesia after thoracic surgery. [11],[12] These effects were mainly related to the reduction of brain stem sensitization via the vagus and phrenic nerves during thoracic surgery and to the attenuation of postoperative opioid-induced hyperalgesia mediated by the activation of NMDA receptors. [13]

We hypothesized that intravenous ketamine would potentiate continuous intercostal analgesia, therefore improving patient comfort, lung expansion, secretions' clearance, and reducing the consumption of supplemental morphine. The aim of this study was to assess the effect of intravenous low-dose ketamine, when combined with continuous intercostal nerve block, on acute pain and supplemental morphine consumption following thoracotomy.


   Materials and Methods Top


This prospective double-blinded and randomized study was approved by our institutional review board. From August 2009 to May 2010, eighty patients admitted in our hospital with lung cancer and scheduled for elective lobectomy through a posterolateral thoracotomy were eligible for the study. Seventeen patients were excluded because of a history of pre-existing chronic pain or chronic opiate use, a mental disease that may affect their capacity to express perception of pain, a documented cardiac, renal or hepatic insufficiency, and allergy to ketamine, bupivacaine, morphine, or ketoprofene. Three other patients refused to participate in the study.

Twenty-four hours prior to the surgery, patients were instructed in using the hand-held incentive spirometer (Leventon, Barcelona, Spain) and the linear visual analog scale (VAS from 0 for no pain to 100 mm for unbearable pain) for pain assessment. Heart rate, blood pressure, and arterial blood gases on nasal oxygen (5 l/min) were recorded as baseline values. Patients were assigned, by using a random number table, to receive postoperative pain relief either by a continuous intercostal nerve block and intravenous ketamine (group 1) or continuous intercostal nerve block and intravenous placebo (group 2).

Premedication consisted of 50 mg hydroxyzine taken orally 45 minutes prior to induction of general anesthesia. In the operating room, two venous and a radial artery catheters were secured for perioperative infusions and repeated arterial blood sampling respectively. Monitoring included electrocardiography, arterial oxygen saturation, end-tidal carbon dioxide tension, rectal temperature, and invasive blood pressure. anesthesia was induced with intravenous propofol 2 mg/kg and maintained with sevoflurane in oxygen and fentanyl up to a maximal total dose of 5 mg/kg, based on heart rate and blood pressure stability. Vecuronium was used to achieve neuromuscular blockade. A double-lumen endobronchial tube was placed for one-lung ventilation. Before skin incision, patients in group 1 received a bolus dose of ketamine 0.1 mg/kg intravenously followed by continuous infusion of 0.05 mg/kg/h, whereas patients in group 2 had placebo. The study drugs, ketamine (1 mg/ml) and placebo (isotonic saline) were prepared under sterile conditions by the hospital pharmacy in identical containers, marked with the name of the study and consecutive patient numbers. The investigators were blinded to the study solutions. Ketamine and saline infusions were maintained during surgery. Lobectomy was performed by the same surgical team through a postero-lateral thoracotomy without rib or parietal pleural resection. On the completion of lung resection, the parietal pleura were peeled back medially toward the neck of the ribs and laterally for two intercostal spaces above and two below the incision. A 16-gauge disposable Tuohy needle was inserted percutaneously at a site about 3 cm medial to the posterior edge of the wound and advanced until the tip was within the chest cavity. A 19-gauge epidural catheter (Arrow international, Philadelphia, USA) with multiple side holes was introduced in the Tuohy needle and advanced cranially into the extra pleural pocket. The needle was withdrawn, the parietal pleura were reattached to the posterior edge of the wound and the catheter was secured. Before skin closure, intercostal nerve block was initiated in all patients with 20 ml of bupivacaine 0.25% through the intercostal catheter.

Patient's trachea was extubated in the operating room, and transferred to the intensive care unit (ICU) for observation for 24 hours and then to the surgical ward. Standardized respiratory physiotherapy and rehabilitation schedule were applied postoperatively. Chest tubes were kept for 48 hours unless other way indicated. Postoperative pain management during the study period of 72 hours included a continuous infusion of bupivacaine 1 mg/ml at a rate of 0.1 ml/kg/h through the intercostal catheter as well as intravenous paracetamol 1 g and ketoprofen 50 mg every 6 hours in all the patients. Additionally, patients in group 1 continued to have their ketamine intravenous infusion of 0.05 mg/kg/h, whereas patients in group 2 had placebo. Patients reporting a visual analog scale (VAS) pain score at rest ≥40 mm received intravenous sulfate morphine as rescue analgesia. Morphine was titrated by boluses of 2 mg with a lock-out time of 5 minutes and a maximal dose of 0.1 mg/kg/6 h to achieve a VAS pain score at rest ≤40 mm. No other analgesic medication was used during the study period.

Patients' demographic, medical, and surgical data were noted. Two observers (T.S. and K.J.), not involved in the surgical procedure and blinded regarding patients randomization groups, assessed the following parameters every 6 hours (H) from H1 to H 72 postoperatively: I- Visual analog scale pain scores at rest and during coughing; II- Ramsay sedation scores (1=anxious patient, 2=cooperative and tranquil, 3=responding to command, 4=brisk response to stimulus, 5=sluggish response to stimulus, 6=no response to stimulus); III- Adverse effects as blurred vision, hallucination, nightmares, vertigo, or nausea and vomiting (yes/no). In the presence of blurred vision, hallucination, or nightmares, the study drug infusion (ketamine or saline) was definitively stopped. Arterial blood gases on nasal oxygen (5 l/min) were recorded every 12 hours during the study period. Rescue analgesia requirement per patient was documented as the number of intravenous morphine deliveries and cumulative dose of morphine received during the study period. All data were collected in ICU and on the surgical ward.

Statistical analysis was achieved with SPSS 13.0 for Window software. For power analysis, the primary endpoint of the study was VAS pain scores. Based on a pilot investigation in our institution, a sample size of 24 patients in each group was calculated to detect a clinically significant VAS score reduction from 50 mmHg to 30 mmHg with a type 1 error of 5% and a power of 80%. Data were reported as mean values±standard deviation or median with first and third quartiles or number of patients, as appropriate. Analysis was performed on an intent-to-treat basis (as randomized). VAS pain scores and arterial blood gases were compared by one-way analysis of variance (ANOVA) between the two groups. Ramsay sedation scores were compared by the Kruskal-Wallis analysis of the variance test. Patients' demographic, medical, and surgical data and morphine rescue analgesia requirement were compared by unpaired Student's t-test or the Mann-Whitney U-test, as appropriate. The Chi-square test was used to compare sex distribution and the frequency of side effect. P≤0.05 was considered statistically significant.


   Results Top


Sixty adult patients, ASA status II-III, were included in this study. Demographic, medical, and surgical data, presented in [Table 1], were comparable between the study groups. Visual analog scale pain scores were presented in [Figure 1] and [Figure 2]. They were not significantly different between the two groups at any time point of the study, at rest (P=0.75) or during coughing (P=0.70). Morphine rescue analgesia requirement was presented in [Table 2]. Cumulative dose of morphine per patient (17 ± 16 mg vs. 12 ± 17 mg; P=0.2) and number of deliveries per patient (1[1-2] vs. 2[1-3]; P=0.17) during the study period were comparable between the study groups. Arterial blood gases were presented in [Table 3]. Ramsay sedation scores were presented in [Table 4]. No statistical difference was detected between the two groups at any time point of the study for PO2 (P=0.08), PCO2 (P=0.6), or sedation scores (P=0.4). The two groups were comparable regarding the incidence of vertigo (7 vs. 5 patients; P=0.5) or nausea and vomiting (8 vs. 6 patients; P=0.4). Two patients in the ketamine group experienced blurred vision, hallucination, or nightmares during the study period and infusion was stopped. They were kept in the study and there data were analyzed on an intent-to-treat basis. During the study period, no intercostal catheter was dislodged accidentally or removed on purpose.
Table 1: Patients' demographic, medical, and surgical data

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Table 2: Morphine rescue analgesia requirement

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Table 3: Arterial blood gases

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Table 4: Ramsay sedation scores

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Figure 1: Visual analog scale pain scores at rest. Data are presented as mean and SD. No difference between the two groups at any time of the study (P=0.75)

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Figure 2: Visual analog scale pain scores during coughing. Data are presented as mean and SD. No difference between the two groups at any time of the study (P=0.70)

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   Discussion Top


Few studies have assessed the combination of low-dose intravenous ketamine with other analgesia modalities following thoracic surgery. Suzuki et al. have reported that low-dose intravenous ketamine, given at 0.05 mg/kg/h for 72 hours following thoracotomy, potentiates epidural morphine-ropivacaine analgesia. [10] Two other studies have showed that adding small doses of ketamine (0.5-1 mg/ml) to morphine in intravenous patient-controlled analgesia decreases morphine consumption and improves respiratory function after thoracic surgery. [11],[12] Lahtinen et al. have documented that a continuous intravenous infusion of ketamine 1.25 mg/kg/min potentiates opioid patient controlled analgesia following cardiac surgery. [14] Based on the dose regimens in these studies, we assessed the effect of intravenous low-dose ketamine 0.05 mg/kg/h on continuous intercostal nerves block following thoracotomy. Our data indicated that low-dose intravenous ketamine did not decrease pain scores and rescue morphine requirement in patients having continuous intercostal analgesia.

Our results are in agreement with previous studies performed outside the context of thoracic surgery. Ilkjaer et al. did not demonstrate an additive effect of intravenous ketamine, infused at 10 mg/h for 48 hours, on bupivacaine epidural analgesia following renal surgery. [15] Edwards et al. reported that the addition of ketamine at a rate of 5, 10, or 20 mg/h to a continuous infusion of morphine did not significantly improve either analgesia or postoperative lung function in elderly patients following upper abdominal surgery. [16] Other investigators showed that, following orthopedic surgery, low-dose intravenous ketamine 0.15 mg/kg had no beneficial effect on pain scores at rest but that it relieved pain on movement. [17] The inefficacy of ketamine in our study may have two explanations: First, the continuous intercostal nerve block combined with intravenous paracetamol and ketoprofen was very effective and therefore ketamine could not demonstrate an additive analgesic effect. In our institution, intercostal nerve block combined with paracetamol and ketoprofen was the "standard of care" for post-thoracotomy pain control. However, the analgesia provided could still be improved and we tested the hypothesis that intravenous subanesthetic doses of ketamine might be beneficial. Second, ketamine produces dose-related analgesia [18] and its inefficiency in our study may be linked to the low intravenous infusion dose of 0.05 mg/kg/h. Recently, Argiriadou et al. reported that intraoperative infusion of ketamine, at a dose of 0.4 mg/kg/h, enhanced post-thoracotomy analgesia when used in conjunction with thoracic paravertebral ropivacaine. [19] A dose-determining study would be useful to find the optimal dose of ketamine needed to improve pain control in patient with continuous intercostal nerve block.

The use of ketamine may be associated with sedation and psychomimetic adverse effects. Sedation scores, in our study, were comparable between ketamine and placebo groups. Previous reports did not find an increased sedation in patients receiving intravenous low-dose ketamine following surgery. [12],[14],[16],[17] Only Ilkjaer et al. reported a significantly higher level of sedation in patients given intravenous ketamine in combination with epidural bupivacaine after renal surgery. [15] Ketamine psychomimetic side effects include blurred vision, vertigo, hallucination, and nightmares. The presence of these manifestations in patients receiving low-dose ketamine following surgery was previously reported. [10],[14],[15],[16] In our study, two patients in the ketamine group presented psychomimetic adverse effects. This incidence did not reach statistical significance, probably because our investigation was underpowered for side effects outcomes. Nevertheless, the presence of psychomimetic manifestations in the ketamine group is concerning and indicate that intravenous low-dose ketamine should be administered with caution and with frequent evaluation following thoracic surgery.

This study has several limitations. First, rescue analgesia was based on intravenous sulfate morphine and not on morphine patient-controlled analgesia. This later technique would have provided a more accurate evaluation of rescue analgesia requirement. Previous investigations showed that, following thoracic surgery, intravenous low-dose ketamine reduced cumulative patient-controlled analgesia consumption. [11],[12],[14] Second, the evaluation of respiratory outcomes in this study was limited to arterial blood gases and did not include pulmonary function tests or postoperative respiratory complications. Michelet et al. showed that adding low-dose ketamine to morphine for patient-controlled analgesia after thoracic surgery had a positive impact on nocturnal pulse oxymetry and forced expiratory volume but did not change the incidence of respiratory complications. [12] Following cardiac surgery, the use of low-dose ketamine as an analgesic adjunct decreased PaCO2 but did not affect pulmonary function tests. [14] Edwards et al. reported that a combined infusion of morphine and low-doses of ketamine in elderly patients after upper abdominal surgery did not significantly improve lung function. [16] In the recent study of Argiriadou et al., even a higher dose of ketamine 0.4 mg/kg/h, in conjunction with ropivacaine thoracic paravertebral block, did not improve lung function or the duration of intensive care unit and hospital stay. [19] Our study did not show a significant difference in arterial blood gases between ketamine and control groups. Even more, as analgesia was comparable between the two groups of our study, we can speculate that our regimen of low-dose intravenous ketamine will not have an impact on postoperative pulmonary function tests or respiratory complications. As a third limitation, this study did not assess the effect of low-dose intravenous ketamine in conjunction with continuous intercostal analgesia on chronic pain following thoracotomy. Suzuki et al. reported that intravenous ketamine 0.05 mg/kg/h combined epidural analgesia decreased chronic pain 1-3 months after thoracic surgery. [10]

In conclusion, intravenous low-dose ketamine 0.05 mg/kg/h, when combined with continuous intercostal nerve block, did not decrease acute pain scores and supplemental morphine consumption following thoracotomy. The 7% incidence of psychomimetic adverse effects in the ketamine group, although not statistically significant, was concerning. Further dose-determining studies are needed for the optimal infusion rate of ketamine to improve pain control with the least incidence of adverse effects in patient with continuous intercostal nerve block.[Additional file 1]

 
   References Top

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9.Sandler AN. Post-thoracotomy analgesia and perioperative outcome. Minerva Anestesiol 1999;65:267-74.  Back to cited text no. 9
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10.Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology 2006;105:111-9.  Back to cited text no. 10
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11.Atangana R, Ngowe Ngowe M, Binam F, Sosso MA. Morphine versus morphine-ketamine association in the management of post operative pain in thoracic surgery. Acta Anaesthesiol Belg 2007;58:125-7.  Back to cited text no. 11
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12.Michelet P, Guervilly C, Hélaine A, Avaro JP, Blayac D, Gaillat F, et al. Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery: Influence on morphine consumption, respiratory function, and nocturnal desaturation. Br J Anaesth 2007;99:396-403.  Back to cited text no. 12
    
13.Laulin JP, Maurette P, Corcuff JB, Rivat C, Chauvin M, Simonnet G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg 2002;94:1263-9.  Back to cited text no. 13
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14.Lahtinen P, Kokki H, Hakala T, Hynynen M. S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery. Anesth Analg 2004;99:1295-301.  Back to cited text no. 14
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15.Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brennum J, Dahl JB. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth 1998;81:707-12.  Back to cited text no. 15
    
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19.Argiriadou H, Papagiannopoulou P, Foroulis CN, Anastasiadis K, Thomaidou E, Papakonstantinou C, et al. Intraoperative infusion of S(+)-ketamine enhances post-thoracotomy pain control compared with perioperative parecoxib when used in conjunction with thoracic paravertebral ropivacaine infusion. J Cardiothorac Vasc Anesth 2011;25:455-61.  Back to cited text no. 19
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Correspondence Address:
Alexandre Yazigi
Department of Anaesthesia and Surgical Intensive Care, Hotel Dieu de France Hospital, Saint Joseph University, Beirut
Lebanon
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.91479

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