McDonald, Susan B. MD*; Jacobsohn, Eric MD, FRCPC†; Kopacz, Dan J. MD*; Desphande, Seema MD†; Helman, James D. MD*; Salinas, Francis MD*; Hall, R Alan MD‡
Early tracheal extubation after cardiac surgery is often practiced and has been shown to be safe and associated with decreased cost and improved outcome (1–6). Anesthetic techniques designed to accomplish this goal, such as volatile anesthetic-based techniques with small opioid doses, may not provide adequate analgesia in the immediate postoperative period. Intrathecal and epidural analgesia may be effective in this regard (7,8), but to many anesthesiologists, the risk of potential epidural hematoma may outweigh these benefits (9–11). IV opioid therapy is most often used for postoperative analgesia in these patients.
A major source of pain for cardiac surgical patients is the median sternotomy incision and the mediastinal tube sites, especially when less invasive endoscopic vein-harvesting techniques are used. The anterior and posterior branches of the intercostal nerves innervate the sternum. Parasternal infiltration of local anesthetic, therefore, is a possible means of improving early postoperative analgesia, even in anticoagulated patients, and has not been described. This regional anesthetic block may reduce opioid requirements, and thus opioid-induced side effects such as respiratory depression and sedation. We conducted this prospective, randomized, double-blind, placebo-controlled study to examine whether a parasternal block combined with local anesthetic infiltration of the sternotomy wound and tube insertion sites can provide early postoperative analgesia in patients undergoing facilitated tracheal extubation after median sternotomy for cardiac surgery.
After IRB approval and written, informed consent, 20 patients were randomized at Barnes Jewish Hospital (BJH) in St. Louis, MO, and Virginia Mason Medical Center (VMMC) in Seattle, WA. Patients were 18 to 80 yr old and were undergoing either single valve replacement or coronary artery bypass grafting, with or without cardiopulmonary bypass (CPB). Before enrollment, patients were subject to strict exclusion criteria to ensure suitability for early tracheal extubation (Appendix 1). Patients were randomized only if they were hemodynamically stable after successful weaning from CPB or completion of anastomoses for off-CPB procedures (Appendix 1).
Investigational pharmacy was responsible for equal randomization into either the placebo (P) or the treatment (LB) group and for the preparation of the study drug; the investigators and surgeons remained blinded. Randomization was computer generated and was paired and stratified according to the type of surgery. Because the parasternal technique had not been described elsewhere, power analysis was based on a reduction of pain scores after small-dose intrathecal morphine in cardiac surgical patients undergoing a similar volatile-based anesthetic and early tracheal extubation protocol.1 The initial power analysis assumed a 20% reduction with 90% power, and it was estimated that 36 patients would need to be enrolled. Because this analysis was based on a different technique, and was therefore inherently imprecise, an interim analysis of 20 patients was included in the original protocol. In accordance with that protocol, further enrollment ceased once statistical significance was reached for the primary end-point (cumulative morphine use) at the interim analysis. A laboratory processing problem resulted in loss of pharmacokinetic samples for the first four patients randomized to the treatment group; therefore, after study completion, an additional four patients gave consent for the purpose of sampling pharmacokinetic data only.
Before surgery, in the operating room holding area, all patients were instructed in the use of the verbal analog pain scale (VAS), patient-controlled analgesia (PCA), bedside spirometry (Puritan Bennett, Wilmington, MA), and mini-mental status examination (12) (MMSE; composed of standard orientation, verbal, math, and comprehension questions). Baseline arterial blood gas analyses were performed after arterial catheter placement, and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) baseline measurements were obtained with the patient in a semirecumbent position.
All patients had a standardized anesthetic technique that was tailored for early tracheal extubation. Monitoring included the standard ASA monitors, an arterial catheter, a central venous catheter, and a PSA4000 quantitative electroencephalograph monitor (Baxter Healthcare and Physiometrix, Inc., North Billerica, MA). Pulmonary artery catheters and transesophageal echocardiography were used at the discretion of the anesthesiologist. Premedication was limited to small doses of IV midazolam (maximum of 0.02 mg/kg). For anesthetic induction, patients were given sufentanil 0.25 μg/kg IV, sodium thiopental 2–3 mg/kg IV or propofol 2–2.5 mg/kg IV, and rocuronium 0.6–1.0 mg/kg IV. Maintenance of anesthetic included an additional 0.15 μg/kg IV sufentanil at incision and desflurane minimum 0.9 minimum alveolar anesthetic concentration (MAC); rocuronium IV was administered to maintain one or two of four twitches on train-of-four monitoring. Vasoactive drugs were used at the discretion of the anesthesiologist. When CPB was used, desflurane was administered via the oxygenator at 0.9 MAC minimum. Because of desflurane’s rapid recovery profile even on CPB (13), it was imperative that desflurane be detected during CPB at all times in the oxygenator exhaust by using the standard multigas-analysis sampling line (14). Also, the PSA4000 monitor was used to help confirm hypnosis. Desflurane does have a frequent incidence of emergence agitation (15); therefore, at the start of sternotomy closure, patients were switched from desflurane to propofol infusion (25–120 μg · kg−1 · min−1) to facilitate smooth emergence. Ondansetron 4 mg IV was administered at end of surgery for nausea/vomiting prophylaxis.
The components of the parasternal block included anesthetizing the intercostal nerves close to the sternal border, the anterior cutaneous branches of the intercostal nerves, and the deep subcutaneous layers around the chest tube sites. To achieve this, the surgeons performed the parasternal block in a standardized fashion just before sternal wire placement (Fig. 1). Patients received either 54 mL of 0.25% levobupivacaine (LB) (Chirocaine; Purdue Frederick, Norwalk, CT) with 1:400,000 epinephrine or 54 mL of saline (P) (no added epinephrine). First, a series of intercostal blocks were placed just lateral to the sternal border: 2 mL for each of the 5 interspaces bilaterally (total of 20 mL). Then, a continuous line of study solution was infiltrated just above the periosteum along the lateral borders of the sternum: 12 mL per side (total of 24 mL). Finally, 10 mL of study drug was infiltrated deeply and evenly around the mediastinal tubes.
Once the sternum was closed and the mediastinal tubes were connected to suction, neuromuscular blockade was reversed, and the patients were allowed to breathe spontaneously. Morphine was titrated in 2-mg IV increments to maintain a respiratory rate <30 breaths/min. If patients were not ready for tracheal extubation in the operating room, then the propofol infusion was continued until arrival in the intensive care unit (ICU). IV morphine was the only analgesic given in the first 8 h, after which patients could be given ketorolac (15–30 mg IV) for breakthrough pain. If patients required rescue pain medication beyond their PCA lockout, then physician-administered IV morphine in 2-mg boluses was given; if pain continued to be uncontrolled or if significant respiratory depression was evident, then ketorolac was given earlier than 8 h after surgery.
There were strict criteria for tracheal extubation; these included the patient’s being alert enough to follow commands and being hemodynamically stable (systolic blood pressure >90 mm Hg and stable cardiac rhythm), with a tympanic temperature >35.5°C, no active bleeding, VAS ≤5, Sao2 >95% on 0.5 fraction of inspired oxygen, a respiratory rate between 10 and 30 breaths/min, and pH >7.30. Once tracheally extubated, the patient was given an IV morphine PCA (1 mg of morphine IV every 5 min; no maximum lockout).
The total amount of morphine given and the number of PCA demands were recorded. Other end-points measured included VAS scores (scale 0–10) at rest and with cough, need for rescue pain medication, vital signs, need for vasoactive drugs, time to tracheal extubation, bedside spirometry values (FEV1 and FVC), arterial blood gas analysis results, and MMSE scores. These measurements were taken at 1, 2, 3, 4, 8, and 24 h after the end of surgery (defined as when surgical drapes were removed). Plasma LB levels were drawn at the end of injection (time 0); at 5, 15, 30, 45, and 60 min; and at 2, 4, 8, and 24 h after parasternal block injection. Samples were analyzed by using liquid chromatography/mass spectrometry with tetracaine control to determine plasma LB concentrations. The limits of determination were 10 ng/mL, with a coefficient of variation at these limits of approximately 0.7% (16).
Statistical analysis (StatView Version 5.0.1; SAS Institute, Cary, NC) was performed for each of the data end-points and all demographic information. For continuous variables, the unpaired Student’s t-test was used to compare the two groups at each time point of data collection. Repeated-measures analysis of variance (RM-ANOVA) was used to compare these variables across the 24-h time period. Fisher’s exact test was used to compare categorical values between groups. Statistical significance was defined as P ≤ 0.05.
From January 2001 through May 2003, 20 patients were randomized: 11 from BJH and 9 from VMMC. Of the 20 patients, 3 were unable to complete the study: 2 had excessive bleeding and hemodynamic instability requiring prolonged tracheal intubation after surgery, and another, who did not divulge alcohol abuse before surgery, had postoperative delirium tremens. Completing the study were eight patients in the LB group (four from BJH and four from VMMC) and nine patients in the P group (five from BJH and four from VMMC). There was no statistical significance in their demographic characteristics (Table 1).
Morphine use was significantly less in the LB group compared with the P group after surgery (Fig. 2). When analyzed across the 24-h time period by RM-ANOVA, the LB group required significantly less morphine to remain comfortable (P = 0.02). VAS scores at rest or with cough were not significantly different between groups (Fig. 3). Scores on the MMSE were also not significantly different, although there was wide variation; for example, at Hour 2, MMSE scores were 26.2 ± 2.3 in the LB group versus 18.1 ± 10.0 in the P group. Four of nine patients in the P group needed rescue pain medication, compared with none of eight in the LB group (P = 0.08).
Five patients were tracheally extubated in the operating room (two in the LB group and three in the P group), and there was no significant difference in time to tracheal extubation (LB group, 36.4 ± 26.1 min; P group, 38.1 ± 24.1 min; P = 0.9). Postoperative bedside spirometry demonstrated a significant reduction in FEV1 and FVC in both groups when compared with baseline, but not when they were compared with each other (Table 2). The alveolar-arterial O2 gradient and arterial Po2 were significantly better in the LB group at the time of tracheal extubation. Patients in the LB group had higher pH values at 4 h (7.36 ± 0.03 in the LB group versus 7.32 ± 0.03 in the P group; P = 0.009), an effect that, when analyzed by RM-ANOVA, remained throughout the study (P = 0.02). However, the observed acidosis had a metabolic component that could not be specifically explained. Vital signs were not different between groups.
Plasma concentration-time profiles of LB were plotted to determine peak concentration levels (Cmax), time to Cmax, and area under the curve during the time observed. Each patient had two peaks in plasma concentration (Fig. 4A). Patients with Cmax values above the mean Cmax had the earliest peak values, between 0 and 30 min after the end of injection (Fig. 4B).
Early tracheal extubation is a desirable goal for cardiac surgical patients and may lead to better respiratory function, decreased symptoms of depression, and decreased cost and length of ICU stay (1–6). To achieve this goal, the immediate postoperative period is the crucial time to establish stable hemodynamics, alert mental status, and adequate pain control. We investigated the parasternal block with local anesthetic infiltration of the sternotomy wound and mediastinal tube sites as a useful analgesic adjunct in the early postoperative period for facilitating tracheal extubation and reducing opioid requirements; we also investigated the resultant side effects of sedation and respiratory depression.
Patients received a desflurane-based anesthetic with minimal amounts of midazolam and sufentanil that were limited to the beginning of the case. This design allowed for very early tracheal extubation and lessened residual anesthetic as a confounding variable. The investigators were ready to tracheally extubate these patients as soon as possible, even in the operating room when suitable. Such active management may be why no difference was seen between groups in time to tracheal extubation.
Morphine use was significantly less in the patients who received local anesthetic for at least the first four hours after surgery. However, despite this smaller use, there was no significant improvement in the undesirable side effects of opioids. It should be noted that even the parasternal block patients used morphine to cover other discomforts, including bladder irritation from the indwelling catheter. This, along with the small sample size, may be why there was a less dramatic effect on the other clinical end-points studied. For example, we included the MMSE as a measure of sedation. Despite a trend toward better scores in the treatment group, no statistically significant difference was seen. We believe that the small number of patients, and thus large standard deviations, did not allow significance to be revealed.
The effect of the parasternal block on respiratory function was also studied. Patients who had parasternal blocks did have better oxygenation at the time of tracheal extubation, a trend that continued throughout the 24-hour period. This may suggest a reduction in splinting with tidal-volume breaths and, therefore, atelectasis. However, bedside spirometry values were no better in the treatment group. Although local anesthetic was infiltrated around the mediastinal tube sites, intrathoracic irritation was not covered well. These tubes may have been the source of discomfort with the deep inspiratory maneuver and a reason why spirometric volumes were not improved with the block.
It was not unexpected that the reported VAS scores would not be statistically significant after tracheal extubation. Patients will titrate PCA medication to bring their pain to tolerable levels. Although the PCA morphine was adequate supplementation for the patients receiving LB, close to half of the P group needed rescue pain medication. Although statistical significance was not reached with this small sample size, it may be a further indication that the parasternal block provided better analgesia than conventional IV therapy alone.
LB was selected as the local anesthetic because of its long duration, which is similar to that of racemic bupivacaine but with less cardiotoxicity (17,18). No threshold level for toxicity of LB has been widely accepted, but much larger concentrations have been tolerated than were reached in this study (16,18). Bardsley et al. (19) studied the cardiovascular effects of IV LB in healthy volunteers and demonstrated tolerance with mean maximum concentrations of 2.62 μg/mL. Our results indicate a biphasic absorption of LB with parasternal infiltration, which may not be unexpected because there are two components to the technique: intercostal injections and subcutaneous infiltration. The first peak may be attributed to the rapid intravascular absorption from the intercostal blocks or, possibly, from partial intravascular injection. This inadvertent intravascular injection is supported by the data shown in Figure 4, in which the largest peak plasma concentrations above the mean occurred within the first five minutes after injection. The second peak was a much slower phase of absorption, perhaps from the tissue-binding affinity of this highly lipid-soluble drug, into the subcutaneous fat. This lipid depot of drug resulted in very low plasma levels that were detectable even 24 hours after injection, and this may suggest “flip-flop” pharmacokinetics that occur when the absorption from the lipid compartment is the rate-limiting step for drug elimination (16). The variability of the plasma concentration-time curves can be mainly attributed to variation in a number of factors, including the patient’s temperature (rewarming phase with increased blood flow to the periphery) and the patient’s need for vasoactive drugs, which might decrease peripheral blood flow and affect cardiac output. Furthermore, it is uncertain what effect the harvesting of the internal mammary artery has on absorption and analgesia.
The pharmacokinetic data suggest that the plasma concentrations reached should be less than potential toxic thresholds. However, the safety of this technique, as with any regional anesthetic block, relies on meticulous application. Potential complications, which are rare and may not be seen in such a small sample size, include pneumothorax and hemothorax or other bleeding complications. To reduce this risk, our surgeons performed the block under direct visualization before sternal wire closure. This timing also allowed them to inspect the area for bleeding before chest closure. They were also careful not to place the needle too far lateral from the sternal border. Verifying negative aspiration during the intercostal block injections should minimize the inadvertent intravascular injection that might occur.
Even though this study was prospective, randomized, double-blind, and placebo controlled, there were limitations. The strict exclusion criteria made recruitment difficult. Patients who were enrolled were not always randomized if intraoperative complications occurred. Because a select group was studied, the results may not be applicable to the general cardiac surgical population. Halting enrollment at the interim analysis made the groups small enough that statistical significance may have been lost for some clinical end-points that may have been evident with larger numbers. However, even with this limited sample size, statistical significance was reached for our primary end-point of cumulative morphine use. Although the presence of a block was not tested because of the surgical dressings, the significant reduction in morphine use in the LB group is a strong indication that analgesia was present.
In conclusion, parasternal block and infiltration of LB in the sternotomy wound and mediastinal tube sites can be a useful analgesic adjunct in the first four to six hours after cardiac surgery. This early postoperative period is crucial in allowing for early tracheal extubation and in establishing recovery milestones. This block reduces opioid requirements, which may have a positive effect on recovery, such as better oxygenation. This regional anesthetic technique is simple, relatively noninvasive, and quickly performed, and unlike neuraxial blocks, it can be used in patients who are anticoagulated perioperatively.
The authors thank Charl de Wet, MD, Laureen Hill, MD, Ralph Damiano, MD, Michael Pasque, MD, Marc R. Moon, MD, Hendrick Barner, MD, Bill Campbell, PA-C, Mary Ditkoff, PA-C, MPAS, Jebadurai Ratnaraj, MD, and the Pain and Toxicity Research Group at the Fred Hutchinson Cancer Research Center.
Preenrollment exclusion criteria were as follows:
1. Allergy to local anesthetics or morphine.
2. Inability to use the patient-controlled analgesia device.
3. Clonidine use.
4. Large-dose steroids.
5. Opioid or benzodiazepine tolerance.
6. Emergency surgery.
7. Previous sternotomy.
8. Combined valve and coronary artery bypass graft surgery.
9. Anticipated cardiopulmonary bypass graft (CPB) time >2.25 h.
10. Ejection fraction <40% or current uncompensated congestive heart failure.
11. Any comorbid medical condition that would make early extubation untenable:
* Neuromuscular diseases.
* Forced expiratory volume in 1 second <50% predicted or Pco2 ≥45 mm Hg.
* Known or anticipated difficult airway.
* Body mass index >35 kg/m2.
* Preoperative inotropic drugs, intraaortic balloon pump, or mechanical ventilation.
* Preexisting coagulopathy.
Postenrollment but prerandomization exclusion criteria were as follows:
1. Use of lidocaine infusions during surgery and/or postoperatively.
2. Continued inotropic support other than small-dose epinephrine (≤1 μg/min) or dobutamine (<2 μg · kg−1 · min−1).
3. Pao2 <100 mm Hg on fraction of inspired oxygen ≥0.5.
4. Uncorrected coagulopathy.
5. CPB time >2.75 h.
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