Intrathecal Morphine for Analgesia in Minimally Invasive Cardiac Surgery

A Randomized, Placebo-controlled, Double-blinded Clinical Trial

Richa Dhawan, M.D., M.P.H.; Danisa Daubenspeck, D.O.; Kristen E. Wroblewski, M.S.; John-Henry Harrison, M.D.; Mackenzie McCrorey, M.S.P.A.C.; Husam H. Balkhy, M.D., Mark A. Chaney, M.D.


Anesthesiology. 2021;135(5):864-876. 

In This Article


All 140 patients scheduled for elective totally endoscopic CABG (June 19, 2018, through August 31, 2020) were assessed for eligibility (Figure 2). Of the 140 patients, 51 did not meet inclusion criteria: coagulopathy (n = 13), body mass index greater than 35 kg/m2 (n = 9), left ventricular ejection fraction less than 40% (n = 9), severe pulmonary disease (n = 6), renal dysfunction (n = 5), anticipated postoperative extubation due to case complexity (n = 5), previous cardiothoracic surgery (n = 2), anticipated CPB support (n = 1), or preoperative cardiac support (n = 1). Ten patients declined.

Figure 2.

Consolidated standards of reporting trials diagram. PCA, patient-controlled analgesia.

The remaining 79 patients were randomized to the morphine (n = 37) or placebo (n = 42) group and included in the final analysis. A per-protocol analysis was performed. There were no instances of a traumatic spinal procedure with return of blood via the spinal needle. Free return of clear cerebrospinal fluid was unattainable in three patients (two morphine, one placebo). These three failed spinal patients were included in preoperative data analysis only and excluded from intraoperative and primary/secondary outcomes analysis. In six patients (two morphine, four placebo), extubation was not possible during the intraoperative or immediate postoperative period. These patients were included in preoperative/intraoperative data analysis and excluded from primary/secondary outcomes analysis. One placebo patient received postoperative PCA morphine, yet the data were lost. This patient was only excluded from primary outcome analysis.

Baseline preoperative characteristics and intraoperative data are presented in Table 1 and Table 2, respectively. The two groups had similar preoperative characteristics and intraoperative anesthetic management. Time from intrathecal dose to administration of IV heparin was similar in both groups (morphine 3 h [2.8 to 4], placebo 3 h [2.6 to 3.8]). Fifty patients were targeted by surgeon/anesthesiologist for intraoperative extubation (22 [63%] morphine, 28 [68%] placebo; P = 0.806) and were successfully extubated. Of these 50 patients, significantly fewer morphine patients required fentanyl after extubation than placebo patients (6 [27%] vs. 19 [68%]; P = 0.004). Twenty-six patients were targeted for immediate postoperative extubation (13 [37%] morphine, 13 [32%] placebo). These patients were not extubated in the operating room for the following reasons: surgeon's concern for bleeding (eight morphine, seven placebo), hemodynamic instability (three morphine, three placebo), hypoxemia (one morphine), pulmonary edema (one morphine), and respiratory acidosis (three placebo). Of these 26 patients, immediate postoperative extubation was successful in 21 patients (11 [42%] morphine, 10 [38%] placebo), and median extubation time from ICU arrival was equivalent between groups (morphine 5 h [2.5 to 7], placebo 4.5 h [3.5 to 6.5]; P = 0.834). Six patients required overnight mechanical ventilation (two morphine, four placebo). Clinical reasons included hemodynamic instability (one morphine, two placebo), pulmonary edema (one morphine), and respiratory acidosis (one placebo). One placebo patient underwent intraoperative extubation yet required immediate postoperative reintubation due to bleeding (extubated the next day).

Primary Outcome

Postoperative morphine requirements are presented in Table 3. Of the 69 patients assessed, 23 received the IV fentanyl protocol (11 [16%] morphine, 12 [17%] placebo), and 46 received the IV morphine protocol (22 [32%] morphine, 24 [35%] placebo). Morphine patients required significantly less IV morphine PCA (26 mg [18 to 36] vs. 50 mg [37 to 77]; P < 0.001), significantly fewer patients required ketorolac (13 [39%] vs. 26 [72%]; P = 0.006), and significantly fewer median tramadol tablets were needed (P = 0.04). During surgical ward stay, significantly fewer morphine patients required oral analgesics when compared to placebo patients (15 [46%] vs. 25 [69%]; P = 0.044). Morphine patients required significantly fewer morphine equivalents during the initial 24 h (28 mg [16 to 46] vs. 59 mg [41 to 79]; P < 0.001), the second 24 h (0 mg [0 to 2] vs. 5 mg [0 to 6]; P < 0.001), and during the entire 48 h (28 mg [16 to 48] vs. 63 mg [43 to 84]; P < 0.001).

Secondary Outcomes

Pain scores, side effects, and patient satisfaction questionnaire results are presented in Table 4, Table 5 and Table 6, respectively. Pain scores at rest and cough were significantly lower in the morphine group (rest median, 0 to 2.5; cough median, 1.5 to 3) than in the placebo group (rest median, 4.5 to 8; cough median, 7 to 10; rest, P < 0.001 to 0.028; cough, P < 0.001 to 0.009; Figure 3). In sensitivity analyses, for both rest and cough, there was a statistically significant overall treatment effect (–4.1 [95% CI, −4.9 to –3.3], and –4.7 [95% CI, −5.5 to –3.9]), respectively with P < 0.001, based on 6 degrees of freedom tests from mixed-effects models including all timepoints (appendix 2).

Figure 3.

The box-plot displays the median (line within box), 25th to 75th percentiles (bottom to top edge of box), and the 25th percentile –1.5 (interquartile range) to the 75th percentile +1.5 (interquartile range; whiskers) of pain scores at 1, 2, 6, 12, 24, and 48 h at rest and cough between the morphine and placebo groups. For both rest and cough, the overall treatment effect gave P < 0.001 (based on 6 degrees of freedom tests from mixed-effects models).

While no patient in either group vomited, more morphine patients experienced mild nausea compared to placebo patients (12 [36%] vs. 3 [8%]; P = 0.004). All instances of nausea and/or pruritus were reported as mild and were treated with ondansetron and hydroxyzine, respectively. One placebo patient required straight catheterization after Foley catheter removal. There were no instances of prolonged intubation secondary to hypercarbia and/or escalation of respiratory support after extubation thought to be secondary to hypercarbia (respiratory depression) in either group.

Sixty-three patients completed the Revised American Pain Society Outcome Questionnaire (28 [85%] morphine, 35 [95%] placebo). Reasons for loss of data were early hospital discharge (two morphine, two placebo) and completed questionnaires being lost (three morphine). While overall satisfaction was high in both groups, results from the questionnaire support the analgesic benefits of intrathecal morphine. When compared to placebo patients, morphine patients had significantly lower "least pain" scores (P = 0.007) and significantly lower "worst pain" scores (P = 0.002), they spent significantly less "percent time in severe pain" (P = 0.003), and they reported significantly more "percentage pain relief in prior 24 h" (P = 0.015).

Overall, patients in both groups experienced a relatively uneventful postoperative course. Three patients developed new-onset atrial fibrillation (one morphine, two placebo), and one patient in each group exhibited postoperative respiratory insufficiency due to hypoxemia. There were no differences between groups regarding ICU length of stay (morphine median, 24 h [21 to 27] vs. placebo median, 24 h [22 to 27]; P = 0.241) or median hospital length of stay (morphine, 2 days [1.6 to 2] vs. placebo, 2 days [2 to 2]; P = 0.833).