Work

Intraoperative targeted blood pressure management and dexmedetomidine on composite complications in moderate-to-high risk patients after major abdominal surgery

Year: 2024

Type: article

Abstract: To the Editor: Postoperative organ injuries and complications are the leading causes of perioperative morbidity and mortality. Although many retrospective studies have revealed the association between intraoperative hypotension and perioperative organ injury,[1] the results of prospective randomized trials with regard to tight blood pressure management and clinical outcomes were inconsistent.[2–4] Organ injury could be also provoked by surgery-induced stress. Dexmedetomidine has been validated to attenuate the over-expression of stress mediators; however, whether perioperative dexmedetomidine can improve clinical outcomes remains uncertain.[5,6] Therefore, this 2×2 factorial randomized trial was designed to investigate whether targeted blood pressure management with/without dexmedetomidine administration could minimize the occurrence of a composite of major organ injuries and complications within 30 days in moderate-to-high risk patients after major non-cardiac surgery. The study protocol was approved by the Biomedical Research Ethics Committee of Peking University First Hospital (2019-73) and registered with ClinicalTrials.gov (NCT03933306). Written informed consent was obtained from all participants or their legal representatives. In this trial, patients with an acute kidney injury (AKI) risk index classification ≥ III who were scheduled for major abdominal surgery were enrolled and randomly allocated into four arms (1:1:1:1) receiving targeted or routine blood pressure management and dexmedetomidine or placebo. For patients assigned to targeted blood pressure management, systolic blood pressure (SBP) was maintained within 10% from baseline by titrating norepinephrine. For the patients assigned to routine blood pressure management, vasoactive agents (ephedrine, phenylephrine, or metaraminol) were injected intravenously when their SBP was lower than 90 mmHg or 30% from baseline. For the patients assigned to dexmedetomidine, a loading dose of 0.6 μg/kg dexmedetomidine was given within 10 minutes, followed by a continuous infusion rate of 0.5 μg·kg−1·h−1 until 1 hour before the end of surgery. Given that anesthesiologists had to implement the designated blood pressure management strategy, they were merely blinded to dexmedetomidine or placebo administration. The accessor-blinded method was adopted to avoid potential bias. Details of inclusion/exclusion criteria, group allocation and blind method, anesthesia management, and postoperative follow-up are provided in Supplementary Methods, https://links.lww.com/CM9/C196. The primary outcome was a composite of organ injuries including acute kidney injury, myocardial injury, delirium, and other serious complications occurring within postoperative 30 days. The secondary outcomes included the incidence of the composite endpoint within postoperative 7 days, intensive care unit admission, duration of hospitalization, and 30-day mortality after surgery. The sample size was calculated with PASS 11.0 software (NCCS, LLC, Kaysville, Utah, USA). A sample size of 496 patients (124 in each group) was required to detect a 28% relative reduction in postoperative complications for both targeted blood pressure management and dexmedetomidine with the significance level at 0.05, power at 0.8, and a follow-up loss rate of 10%. Detailed information for sample size calculation and statistical analysis are provided in Supplementary Methods, https://links.lww.com/CM9/C196. From May 2019 to October 2020, 496 patients were randomized (124 patients in each arm, Supplementary Figure 1, https://links.lww.com/CM9/C196). Baseline data and perioperative variables were well balanced between groups. The exemptions were as follows: the patients assigned to targeted blood pressure management received more vasopressors (mainly norepinephrine) and experienced fewer hypotensive episodes compared with those in the control group; and the patients randomized to dexmedetomidine administration were given less sevoflurane and experienced fewer hypertensive episodes during anesthesia compared with those in the placebo group [Supplementary Tables 1–4, https://links.lww.com/CM9/C196]. Logistic regression analyses showed no significant interaction between targeted blood pressure management and dexmedetomidine administration (P = 0.860 in the intention-to-treat analysis; P = 0.843 in the per-protocol analysis). The incidence of the composite endpoints was 37.5% (93/248) in the patients with targeted blood pressure management and 42.3% (105/248) in those with routine care (risk ratio [RR], 0.89; 95% confidence interval [CI], 0.71–1.10; P = 0.217, Figure 1A). Subgroup analyses did not identify significant interactions between targeted blood pressure management and any predefined factors [Supplemental Figure 2A, https://links.lww.com/CM9/C196]. Secondary and other outcomes were not significantly different between the groups [Supplementary Figure 3A; Supplementary Tables 5 and 6, https://links.lww.com/CM9/C196].Figure 1: The cumulative incidence of postoperative complications in patients with targeted blood pressure management (A) or with dexmedetomidine (B) was comparable with those in routine care group.The incidence of the composite endpoints within 30 postoperative days was 40.7% (101/248) in the patients administered with dexmedetomidine and 39.1% (97/248) in those given placebo (RR, 1.04; 95% CI, 0.84–1.29, P = 0.714; Figure 1B). Subgroup analyses did not identify significant interactions between dexmedetomidine administration and any predefined factors [Supplementary Figure 2B, https://links.lww.com/CM9/C196]. No significant differences in secondary and other outcomes were found between the groups [Supplementary Figure 3B; Supplementary Tables 5 and 6, https://links.lww.com/CM9/C196]. With regard to safety outcomes, the patients assigned to targeted blood pressure management developed less severe intraoperative hypotension than those assigned to routine blood pressure management (12.5% [31/248] vs. 22.2% [55/248]; P = 0.004). The patients administered with dexmedetomidine experienced less intraoperative tachycardia (1.2% [3/248] vs. 5.2% [13/248]; P = 0.011) and less severe hypertension (15.7% [39/248] vs. 24.2% [60/248]; P = 0.018), but more intraoperative bradycardia (10.5% [26/248] vs. 4.8% [12/248]; P = 0.018; Supplementary Table 7, https://links.lww.com/CM9/C196). The definitions of intraoperative hypotension vary widely. We defined the relative hypotensive threshold similarly to the INPRESS trial[2] and considered blood pressure at rest in the general ward as baseline reference. In this study, mean SBP was 6 mmHg (95% CI, 4–8 mmHg) higher in the patients assigned to targeted blood pressure compared with that in the patients receiving routine care. This difference was nearly identical to that in the INPRESS trial.[2] Consequently, the cumulative duration of SBP <90% of baseline was 49 min (95% CI, 29–52 min) shorter in this group. However, hypotension avoidance was possibly less effective in our trial because our patients were at lower risk than those in the INPRESS trial. For example, the patients classified as AKI risk index grade IV or higher comprised 30% of our population and 50% that of the INPRESS study.[2] Besides, we adopted the routine care of blood pressure management strategy in the control group based on a previous study which showed that a decrease of SBP to <90 mmHg was associated with increased risks of adverse outcomes.[1] The blood pressure management strategy was less permissive and the mean SBP was higher in our control patients compared with those in the INPRESS trial (128 ± 13 mmHg vs. 116 ± 24 mmHg).[2] This might compromise the intervention effect. Two recent trials reported that intraoperative blood pressure management strategies could not reduce the risk of postoperative complications including myocardial injury, major cardiovascular events, stroke and AKI.[3,4] Our results showed that the incidence of pneumonia was significantly low in patients assigned to targeted blood pressure management. Similar findings were reported by Futier and colleagues.[2] However, we could not obtain a robust conclusion because of the limited sample size. The effect of dexmedetomidine on perioperative complications remains unclear. One complexity is that dexmedetomidine induces hypotension and this effect might be associated with organ injury and various complications. A strength of our trial is that, because of its factorial design with targeted blood pressure control, the incidence and duration of hypotension were well balanced in the patients administered with dexmedetomidine and placebo. The patients enrolled in our trial were slightly younger, had shorter durations of anesthesia and surgery, and developed less delirium than those in a previous dexmedetomidine trial.[5] Nevertheless, with 198 patients suffering postoperative complications, we have sufficient power to conclude that intraoperative dexmedetomidine administration did not decrease the incidence of composite endpoint in our patients. This could be attributed to the fact that intraoperative dexmedetomidine produced only transient effects on surgical stress.[6] In summary, targeted blood pressure management did not significantly reduce our composite endpoints which included AKI, myocardial injury, delirium, and other major complications. The observed 11% relative risk reduction seems clinically meaningful but needs to be confirmed in a larger trial. In addition, intraoperative dexmedetomidine did not reduce composite endpoints after surgery. Fundings This study was supported by grants from the National Key Research & Development Program of China (Nos. 2023YFC2506900 and 2018YFC2001800), the National High Level Hospital Clinical Research Funding (Nos. 2022CR74 and 2022CR78 of Peking University First Hospital), and Braun Anesthesia Scientific Research Fund (No. BBDF-2019-004). Conflicts of interests None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003349