Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects

https://doi.org/10.1016/j.phrs.2008.06.003Get rights and content

Abstract

Background

Thoracotomy is associated with severe pain. Large doses of morphine can depress respiratory drive and compromise hemodynamic stability. Ketamine reduces hyperalgesia, prevents opioid tolerance and resistance and lowers morphine consumption. At sub-anesthetic (≤500 μg/kg) doses, ketamine rarely produces undesirable hemodynamic alterations. We hypothesized that by combining a sub-anesthetic dose of ketamine with morphine, we could effectively control pain with less morphine and minimize drowsiness, while maintaining safe hemodynamic and respiratory parameters.

Methods

Sequential patients undergoing anterolateral thoracotomy for MIDCAB, lung tumor resection, or median sternotomy for OPCAB were randomized to one of the two intravenous patient-controlled analgesia (IV-PCA) protocols. MO-only patients received 1.5 mg MO bolus, and MK patients received 1.0 mg MO + 5 mg ketamine/bolus, both with a 7 min lockout time. IV-PCA was initiated when the patient was sufficiently awake (≥5/10 VAS) and rated pain ≥5/10 on a 0–10 VAS. Rescue intramuscular diclofenac 75 mg was available. Follow-up of respiratory, hemodynamic and pain statuses lasted 72 h.

Results

Fifty-eight patients completed the 6-month study. Heart rate and blood pressures were identically stable in both groups. Respiratory rate and pulse oximetry were higher (P < 0.05) in the MK than in the MO group. MO patients (n = 28) used twice (2.0 ± 2.3 mg/patient/h) the amount of morphine compared to MK patients (n = 30, 1.0 ± 1.4 mg/patient/h, P < 0.05). Thirty-six hours after starting PCA, 10 MO patients still required IV-PCA compared to 5 MK patients (P < 0.05). Diclofenac was used 70% more in MO than in MK patients. MO patients suffered more postoperative nausea and vomiting. No patients had hallucinations.

Conclusions

The concomitant use of sub-anesthetic ketamine plus two-thirds the standard MO dose following thoracotomy, MIDCAB or OPCAB resulted in lower pain scores, reduced MO consumption and shorter postoperative IV-PCA dependence. These advantages were associated with cardiovascular stability and even better respiratory parameters.

Introduction

Thoracotomy, whether performed for the resection of lung tumor or for coronary revascularization either by MIDCAB or via OPCAB, is associated with severe and sometimes debilitating pain [1], [2]. Catecholamine release in response to nociceptive stimuli [3] in these patients is associated with undesirable hemodynamic consequences as well as disturbances in respiratory, endocrine, metabolic [4] and immune functions [5]. These changes may increase the rate of complications, prolong hospitalization and raise costs. Importantly, if acute pain is not effectively controlled, it may evolve into severe, chronic pain [6].

Postoperative pain that is uncontrollable despite the administration of considerable amounts of IV morphine could suggest tolerance to the drug [7], [8], [9]. The administration of large amounts of morphine to the awakening patient may cause respiratory and hemodynamic depression [10], [11]. These effects may be especially serious when they follow lung lobectomy [2] or when they occur in patients with poor left ventricular function [12], [13]. For these reasons, supplementation of morphine with non-narcotics (adjuvant agents) may be a preferred way of effectively controlling pain while reducing the incidence of adverse events [14], [15].

Ketamine, a non-competitive NMDAR antagonist, was shown to enhance opioid-induced acute antinociception [16]. It was also shown to reduce hyperalgesia, prevent opioid tolerance in animals [17] and lower morphine resistance in humans [18]. The concomitant administration of the two drugs also lowered morphine consumption both in the immediate and delayed postoperative period [19]. Given that sub-anesthetic (≤500 μg/kg) doses of ketamine rarely produce undesirable hemodynamic alterations (e.g., elevated heart rate and blood pressure) [20], we hypothesized that by combining a sub-anesthetic dose of ketamine with morphine, we could effectively control pain with less morphine and thereby minimize drowsiness with no detrimental effect upon hemodynamic stability or respiration.

Section snippets

Patients and methods

After the study protocol was approved by the Ethics Committee of the Tel-Aviv Sourasky Medical Center, 60 patients scheduled for elective MIDCAB or OPCAB or for lung resection via anterolateral thoracotomy during March–September 2004 were enrolled. They all gave their informed, written consent to participate in this prospective, randomized, double blind study and were assigned to one of two groups according to their national ID number. Exclusion criteria were ASA physical class >3, emergency

Results

Sixty patients fulfilled the study criteria for randomization (Table 1). Two of them (one in each of the two groups) subsequently dropped out of the study because they required continuous ventilation. The data of another MK patient were not analyzed because the patient was brought back to the operating theater to control postoperative bleeding (CONSORT Statement, Fig. 1). The demographic, anesthesia and surgical data were similar between the study groups (Table 1), as were intraoperative blood

Comment

Our study demonstrated that the administration of 5 mg ketamine combined with 1 mg morphine per bolus of IV-PCA (MK group) controlled pain better than the “standard” 1.5 mg morphine/bolus of IV-PCA (MO group). Adjuvant ketamine spared morphine consumption by 50%, allowed for a shorter period of dependence on IV-PCA, and was associated with better respiratory parameters compared to morphine alone during the 72 h after thoracotomy. The combined protocol was also associated with remarkably stable

Acknowledgements

The authors thank the medical and nursing staff of the Cardiothoracic Surgery Department for their collaboration and dedication. Esther Eshkol, MA, is thanked for linguistic and editorial assistance.

References (30)

  • W.J. Phillips et al.

    Analgesic pharmacology: II. Specific analgesics

    J Am Acad Orthop Surg

    (2004)
  • M.H. Fleron et al.

    A comparison of intrathecal opioid and intravenous analgesia for the incidence of cardiovascular, respiratory, and renal complications after abdominal aortic surgery

    Anesth Analg

    (2003)
  • B. Beilin et al.

    The effects of postoperative pain management on immune response to surgery

    Anesth Analg

    (2003)
  • V. Raghavendra et al.

    Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats

    Neuropsychopharmacology

    (2004)
  • J. Mao

    Opioid tolerance and neuroplasticity

    Novartis Found Symp

    (2004)
  • Cited by (0)

    This study was presented in part at the Euroanaesthesia 2003 Meeting, Glasgow, Scotland and at the 20th International Congress of the Israel Society of Anesthesiologists, 2005, Tel Aviv, Israel.

    View full text