Author: anesthesiaexperts-admin

Thank you for thoroughly examining our study and for giving us the opportunity to discuss the points you raised regarding our research published in Anesthesia & Analgesia. These issues were extensively discussed during the peer review process, which included robust dialogue with the reviewers and the assigned statistical reviewer. This invitation to respond allows us to further elucidate the scientific rigor and validity underpinning our work.

SAMPLE SIZE AND STATISTICAL RIGOR

Based on previous studies, our initial sample size calculation aimed to detect a clinically meaningful difference in total remifentanil dose was initially set at 200 µg. As the study progressed, we adapted the metric to µg/kg/min to better account for patient body weight and procedural duration. Despite these changes, the original sample size retained sufficient power for robust analysis. On consultation during peer review, we applied Bonferroni correction, adjusting our alpha to 0.025 for each primary outcome. This rigorous adjustment ensured a conservative approach to significance testing, enhancing the reliability of our findings.

ANESTHETIC DOSE MANAGEMENT

The reduction in anesthetic doses correlates with improved hemodynamic stability, demonstrating that Autonomic Neural Blockade (ANB) effectively modulates surgical stress responses. This is reflected in the significant reduction in opioid consumption, which, although quantitatively small at 0.04 µg/kg/min, carries substantial clinical importance within the context of the opioid crisis and opioid-sparing initiatives in perioperative care. The total mean difference observed was 182.9 µg, reinforcing its clinical relevance.

PROTOCOL ADHERENCE AND CLINICAL AUTONOMY

While an independent investigator monitored protocol adherence in our study, treating anesthesiologists retained clinical autonomy to adjust anesthesia based on real-time patient needs. Variations in anesthetic administration, such as one anesthesiologist’s increased use of sevoflurane over remifentanil, were based on clinical judgments aimed at optimizing patient care and safety, not a protocol failure. Deviations were documented and analyzed to ensure transparency in how clinical decisions influenced study outcomes, adhering to safety and ethical standards within operational research constraints.

HEMODYNAMIC IMPACT AND CLINICAL STABILITY

In our study, changes in mean arterial pressure (MAP) and heart rate (HR) were not only statistically significant but also clinically meaningful. The group that exhibited improved hemodynamic stability—with a decrease in MAP of 8.2 mm Hg vs 0.6 mm Hg and a reduction in HR of 3.3 beats/min versus an increase of 4.8 beats/min—also received fewer anesthetics due to the early application of ANB. This correlation strongly suggests that ANB reduces the need for anesthetics and enhances physiological stability during surgery. All hemodynamic measurements were taken at 3 critical surgical moments, with careful control for confounding factors like hypertension, age, BMI, and chronic analgesic use across both groups, as detailed in Table 1. This meticulous approach confirms that the observed hemodynamic benefits are directly attributable to ANB, enhancing both patient safety and surgical efficiency.

FOCUS ON ANESTHETIC AGENTS

Our study primarily highlighted remifentanil due to its profound implications for opioid management. Although the less emphasized difference in sevoflurane consumption did not reach statistical significance, it remains an integral part of our comprehensive evaluation of anesthetic agent use. This choice underscores our focus on outcomes significantly affecting patient recovery and safety.

BLINDING AND RANDOMIZATION INTEGRITY

Blinding was meticulously maintained for patients and data collectors, with only the surgical and anesthesiology teams unblinded to ensure the safe management of interventions. Our randomization effectively balanced all significant demographic and clinical variables, as confirmed by the absence of significant differences in baseline characteristics (Table 1).

ADDRESSING POTENTIAL BETA-BLOCKER COMPARISONS

The changes in hemodynamic parameters like mean arterial pressure and heart rate were statistically significant and clinically relevant. The improvement in these parameters demonstrates the efficacy of ANB when applied early in surgery. Unlike beta-blockers, which primarily modulate cardiovascular responses, ANB provides a comprehensive sensory blockade that reduces physiological stress responses, offering a broader range of perioperative benefits than beta-blockers alone.

We hope this response addresses your concerns and clarifies our study’s methodologies and outcomes. We remain committed to advancing surgical anesthesia practices through rigorous research and innovative approaches like ANB.

To the Editor

We read with great interest the recently published randomized controlled trial describing the impact on anesthetic agent consumption after autonomic neural blockade (ANB) as a part of combined anesthesia protocol in laparoscopic sleeve gastrectomy (LSG). We commend Daes et al for studying the effect of the timing of the novel ANB, at the onset of LSG (early ANB) compared to performing the ANB at the end (late ANB). They reported a significant reduction in intraoperative remifentanil consumption when ANB was performed at LSG onset.

The sample size was calculated to detect a between-group difference of 200 µg (target effect estimate) in total remifentanil dose. The primary outcome during the study had been changed to remifentanil in µg/kg/min. However, the target effect estimate in the sample size calculation was not normalized to body weight and time. Although this change occurred during the course of the study, the sample size should have been recalculated for a minimum clinically important difference (initially defined as 100 µg total) in terms of µg/kg/min. In addition, in the data collection section, sevoflurane consumption was stated as a co-primary outcome but did not receive an a priori power/sample size calculation.

In the statistical analysis section, it is mentioned that the P values for multiple comparisons (of the primary outcomes) were Bonferroni adjusted, setting the significance threshold at P < .025. If this were the case, the sample size calculation should have been performed for an alpha of 0.025 for each primary outcome.

The strategy to modify anesthetic doses was primarily based on hemodynamics, and the results presented in Table 4 show a statistically significant difference in hemodynamics between the groups. This difference could be due to inadequate or overtitration of intraoperative remifentanil and sevoflurane in one of the groups. This reflects a potential failure of the anesthesia protocol. The independent investigator who collected the data was also responsible for ensuring that the opioid and sevoflurane protocols were followed. However, one of the 2 treating anesthesiologists administered more sevoflurane than remifentanil, as stated in the study. This indicates a failure of the anesthesia protocol. The protocol stated that a minimum alveolar concentration (MAC) concentration of 0.4 was used as the lower end for sevoflurane (which can place the patient at risk for awareness) was used as the lower end for sevoflurane, while in the strategy to modify anesthetic doses section, the lower end was mentioned as a MAC of 0.6. Although the bispectral index was monitored, the proportion of intraoperative time spent in the target range of 40 to 60 has not been presented. Had the titration of sevoflurane and remifentanil to hemodynamics adhered to the protocol, there should have been no significant difference in the hemodynamics.

The authors, however, choose to conclude that their intervention significantly stabilizes hemodynamics solely based on P values. The magnitude of these hemodynamic changes was very minor (a change in MAP by 8 mm Hg from 89 mm Hg or 0.5 mm Hg from 87 mm Hg is mostly clinically inconsequential). Interestingly, the difference from baseline appeared to be lower in the late ANB group, suggesting less hemodynamic fluctuation in this group. The hemodynamics could have been affected by other factors such as prior medication (considering that there were 10% and 17% hypertensives in each of the groups) and blood loss, which appear to have not been measured in the study.

The authors mentioned double blinding, but it is unclear who was blinded. Considering that ANB was performed intraoperatively, it is most likely that the patients were blinded, but it is less likely that the surgeon, the treating anesthesiologist, or the person collecting the opioid and sevoflurane consumption was blinded. The independent investigator collecting the study data was not present before the division of the greater omentum, and after the leak test, data were collected during these periods by the treating anesthesiologist, which potentially breaches the blinding. It was stated that the data manager had generated and had access to the randomization list throughout the study. These statements suggest a bias concerning randomization and blinding.

An examination of Table 1 shows a failure of randomization as the standardized differences were quite large for sex, body mass index, and hypertension. These factors are known to affect opioid requirements (and hemodynamics) and providing adjusted estimates would have been meaningful.

In conclusion, the authors claimed a significant reduction in opioid consumption with early administration of ANB. Although the P value for difference in remifentanil consumption is very small P < .001 the difference between groups is 0.04 µg/kg/min (95% confidence interval [CI], 0.02–0.06 µg/kg/min). This was less than the minimum rate of administration in the trial protocol (0.1 µg/kg/min). The between-group mean difference for the total dose comes to 182.9 (95% CI, 16.79–349) µg. The lower end of this CI suggests that the use of early ANB may produce only a minor difference in intraoperative remifentanil dose requirement. This article focuses on statistically significant P values, while the clinical significance of the effect estimate has been ignored.

Although the title of the article reads “Impact on Anesthetic Agent Consumption,” the article focuses mainly on remifentanil consumption, and sevoflurane takes much less space, probably because of P > .05. There appears to be a typo/mismatch in the values presented in the results section of the sevoflurane consumption (mean difference +0.17 mL/min, 95% CI, 0.003–0; P =.088). This should be a difference of 0.01 mL/min (95% CI, −0.010 to 0.03, P = .326 for a t test) based on data in Table 2.

Considering the expertise required to perform the block, the ambiguity around the results (hemodynamics, dosing protocol/practices, baseline differences, and data presentation), and the very small difference in the dose of this short-acting opioid, it would be difficult to conclude that early ANB produces a meaningful reduction in intraoperative opioid consumption or anesthetic agent consumption.

A few important questions arise from this treatment protocol: Does blocking the autonomic response to pain mean less intraoperative and postoperative pain? Does this warrant a reduction in intraoperative analgesic dose? Could the same hemodynamic stability (a lower heart rate/MAP) be replicated using beta-blockers, or does the analgesic effect of this ANB work mainly through a sensory block (essentially a visceral nerve block)?

To the Editor

We read with interest the recent study by Katzi et al evaluating the influences of a single dose of epidural morphine after vaginal delivery on opioid consumption, pain control, and quality of recovery. Other than the limitations described by them in the discussion, we have several questions about their methods and results and wish to get their reply.

First, as a primary outcome of this study, opioid consumption was converted into intravenous (IV) morphine milligram equivalent (MME) for the between-group comparison. However, the MME conversion factors for oral and IV hydromorphone are questionable. Based on the newest guideline of the Centers for Disease Control and Prevention for prescribing opioids for pain—United States, 2022, the oral MME conversion factor of oral hydromorphone is 5 rather than 4 reported in this study. In the current pain management practices, moreover, the recommended oral MME conversion factor for IV hydromorphone is 18. Given that 1 mg IV morphine is equivalent to 3 mg oral morphine, as described by Katzi et al, 1 mg IV hydromorphone should be converted to 6 mg IV morphine. That is, the MME conversion factor of IV hydromorphone to IV morphine should be 6, rather than 3 reported in this study. The lower MME conversion factors for oral and IV hydromorphone used in this study may not only influence the results of between-group comparison regarding 24-hour opioid consumption, but also they can result in difficulty in comparing the results of this study with the findings of other works.

Second, the choice of a 2.5-MME difference in 24-hour opioid consumption as the effector to estimate the sample size was not based on literature evidence or guidelines. In the available literature, the recommended minimal clinically important difference of total opioid consumption for postoperative analgesia in a randomized controlled trial is 10 mg IV morphine in 24 hours. The MME consumed in the 24 hours was statistically decreased in the interventional group, but the median treatment effect was 0, which does not achieve their assumed effector of 2.5 MMEs. Most importantly, opioid consumption is not a patient-centered outcome and cannot imply any patient benefit unless it is matched with improved pain control or decreased side effects such as respiratory depression, nausea and vomiting, dizziness, and delayed gastrointestinal function recovery. Indeed, median pain score at 24 hours was statistically reduced in the interventional group and the between-group difference of median pain scores at 24 hours achieved the minimal clinically important difference of 1 point recommended in available literature. However, median pain scores at 24 hours in the 2 groups were 3 or less, indicating that most patients only experienced a mild pain, that is, a clinically acceptable level of pain control.⁵ In addition, this study did not assess patient satisfaction with postdelivery pain control. Considering the facts that epidural morphine after vaginal delivery resulted in more side effects associated with neuraxial opioid use and did not improve any outcome of postdelivery recovery, we cannot determine if decreased opioid consumption and improved pain control by this intervention are only statistically significant, but clinically insignificant. At least, the clinical importance of using this intervention to enhance recovery after vaginal delivery is questionable.

Finally, in the methods, the authors described that secondary end points included total opioid consumption until discharge and total opioid consumption through week 1 of discharge. However, their results did not report and compare these variables. They reported the rates of opioid use within 24 hours of delivery, but not the time to first opioid need and the time from the completion of epidural morphine to discharge from the hospital. In fact, these outcome variables are useful for the complete evaluation of the analgesic efficacy, duration, and potential benefits of epidural morphine after vaginal delivery.