We read with great enthusiasm the manuscript by Richards et al. titled “Damage Control Resuscitation in Traumatic Hemorrhage: It Is More Than Fixing the Holes and Filling the Tank.”  This comprehensive review significantly contributes to our understanding of resuscitation strategies in traumatic hemorrhage, emphasizing the importance of a multifaceted approach to patient care.

While the manuscript effectively encapsulates various critical aspects of damage control resuscitation, we wish to highlight an area not extensively covered in the discussion—management strategies for patients experiencing the direst consequences of traumatic injuries, including exsanguination cardiac arrest and cardiac arrest caused by blunt cardiac injury, airway trauma, severe pulmonary contusion, and other causes of severe hypoxia. These scenarios necessitate familiarity with the latest advancements in emergency response techniques. Standard resuscitation techniques in these patients are unlikely to produce effective organ perfusion and often result in poor outcome, with mortality of nearly 100% reported for certain types of exsanguination cardiac arrest. For patients without exsanguination as the predominant reason for cardiac arrest, novel resuscitative efforts involving extracorporeal circulation may be required. The use of extracorporeal life support can result in a reasonable survival rate, with one study reporting a 70% survival.  Although venovenous–extracorporeal membrane oxygenation (ECMO) was employed in a majority of these cases (88.5%), 11.5% underwent venoarterial ECMO (standard venoarterial–ECMO or venoarterial–ECMO for extracorporeal cardiopulmonary resuscitation [CPR]). The authors reported a 50% survival in the patients who underwent conventional venoarterial–ECMO and 25% survival in patients who received extracorporeal CPR, in line with extracorporeal life support survival rates in nontrauma patients from the Extracorporeal Life Support organization registry (44% survival for non–extracorporeal CPR cardiac support and 30% survival for extracorporeal CPR).  These findings underscore that trauma should not be considered a contraindication for extracorporeal life support. Moreover, in trauma patients, where systemic anticoagulation is often not feasible, the use of heparin-coated circuits presents a tailored approach in navigating the challenges of associated hemorrhage and hypovolemia. While extracorporeal life support is not a direct treatment for hemorrhagic shock or exsanguination cardiac arrest, it can be a valuable tool in managing postresuscitative myocardial suppression from acidosis, hypothermia, electrolyte abnormalities, citrate toxicity, and transfusion-associated acute lung injury.

The innovative work by Tisherman et al.  on emergency preservation and resuscitation for exsanguination cardiac arrest introduces a pioneering approach to trauma care. Their feasibility study on emergency preservation and resuscitation utilizes profound hypothermia to extend the time available for surgical intervention before irreversible organ damage occurs, demonstrating significant improvements in survival and neurologic recovery.

For trauma patients with non-exsanguination cardiac arrest, extracorporeal CPR can offer a bridge to definitive care by providing circulatory and respiratory support when conventional CPR fails, ideally with cannulation and initiation occurring within 60 min of cardiac arrest. It helps in maintaining oxygenation and perfusion, potentially allowing for the treatment of reversible causes of cardiac arrest and improving the chances of survival and neurologic outcomes by reducing hypoxic or ischemic time of vital organs. In a recent review by Inoue et al.  the potential of extracorporeal CPR to mitigate reperfusion injury and secondary brain damage was highlighted, in addition to the increased chance of successful resuscitation and return of spontaneous circulation, underscoring the need for careful management and future integration of extracorporeal CPR with other therapeutic strategies.

As extracorporeal CPR programs expand, consideration should be provided to the disparities of care that exist currently, those that could be created or exacerbated by emergency preservation and resuscitation, and methods that may reduce existing disparities through extracorporeal CPR. For example, rural trauma victims have higher mortality than nonrural residents. One third of the U.S. population lives further than 45 min away from an ECMO-capable center, and 47% of children in a rural setting live greater than 60 miles from an ECMO-capable center.  Furthermore, application of extracorporeal CPR may be hindered by timely access to personnel skilled at cannulation and initiation of extracorporeal life support. In the absence of exsanguination, extracorporeal life support initiated at a rural or nontrauma center can serve to bridge the patient during transfer to a higher level of care and address current mortality disparities pertaining to patient distance to these centers.

In conclusion, the article by Richards et al. provides an invaluable overview of damage control resuscitation that can be complimented by integrating advancements in extracorporeal life support (including extracorporeal CPR) and emergency preservation and resuscitation (fig. 1). We look forward to seeing these critical aspects of trauma care addressed in future discussions and research.

We were pleased to read the Clinical Focus Review by Richards et al., “Damage Control Resuscitation in Traumatic Hemorrhage: It Is More Than Fixing the Holes and Filling the Tank”  in the March 2024 issue of Anesthesiology. This review is one of the most succinct yet comprehensive discussions of evidence-based trauma resuscitation that we have encountered. As military anesthesiologists, this topic is of particular interest to us. We feel that this will serve as a valuable reference for service members deployed to combat zones. We also look forward to using this article to discuss resuscitation with our residents as a teaching guide.

We do, however, find the term “damage control resuscitation” to be misleading in this context. The U.S. Military has used this term for decades, and its use by Richards et al. here invites confusion. In 2006, the United States Army published clinical practice guidelines for damage control resuscitation.  This term developed as an extension of the concept of damage control surgery, which emphasized hemorrhage control, decontamination, and correction of major physiologic derangements before definitive repair.  Damage control resuscitation practice guidelines recommended a higher than traditional fresh frozen plasma: packed red blood cell transfusion ratio and restrictive crystalloid use. These practices likely contributed to the decrease in trauma mortality during the wars of the last 2 decades.  The concepts of damage control resuscitation were further developed in the military when the Defense Health Agency’s (Falls Church, Virginia) Joint Trauma System advocated for the use of whole blood when available. Among allied military partners, whole blood has similarly been recommended for use.

Resuscitation is the act of reviving the near-dead to a state of hemodynamic stability. Generally, this involves the correction of physiologic abnormalities, including hemorrhage, acidosis, hypothermia, coagulopathy, and electrolyte disturbances. While patients with significant trauma often require rapid, large-volume resuscitation, they are hardly the only patients in need of such resuscitation. All of the techniques and considerations that are described by Richards et al. are likely valid for most surgical patient populations, not just those who undergo traumatic hemorrhage. Our concern is that the damage control resuscitation label may imply that these well-described fundamentals of comprehensive resuscitation are solely applicable to the trauma patient population, and do not necessarily apply to other surgical patients requiring similar resuscitation.

Ultimately, we feel the concept of damage control resuscitation is misleading because there is no “damage control” aspect of the resuscitation, unlike with damage control surgery. No amount of damage control resuscitation will fix or correct damage, whether caused by trauma or otherwise. It is a way to buy time for definitive treatment. Furthermore, “damage” is term not historically applied to people. Structures are damaged; machines are damaged; networks are damaged. Humans are injured. Better terms may include “comprehensive,” “goal-directed,” or “balanced” resuscitation, all of which highlight the broader approach to correcting physiologic derangements than simply transfusing red cells.

Despite our concerns with the terminology used by Richards et al., we would again like to emphasize that their article will serve as a foundational document for anesthesiologists who are deploying into harm’s way, and seek to have the most up-to-date knowledge on how to care for our service members. We would press the authors to consider the use of more inclusive language to ensure that these lessons are applied outside of the trauma-specific patient population as well.

Cardiac surgery is associated with significant postoperative pain. Methadone reduces postoperative pain and opioid consumption after cardiothoracic procedures, but the dosing of intraoperative methadone is unclear.  Our previous investigation of this retrospective cohort found that the use of intraoperative methadone was associated with lower pain scores and lower postoperative oral morphine equivalents after cardiac surgery compared to shorter acting opioids, but we did not examine dosing of methadone.  This secondary analysis of that previous study provides dose–response relationships for methadone administered intraoperatively to cardiac surgery patients for both analgesia and adverse effects.

Details of the study sample have been previously reported, but briefly, this retrospective cohort study (Mayo Clinic Institutional Review Board approval No. 22-007486) included 12,017 adults who underwent cardiac surgery with cardiopulmonary bypass from 2018 to 2023 at a large, multisite healthcare system.  The primary outcome of interest for this analysis was patient- and intensive care unit (ICU) nurse–reported daily mean pain score (0 to 10) until postoperative day 7. The secondary outcomes were daily total postoperative oral morphine equivalents until POD 7 and time until first postoperative opioid administration. Exploratory outcomes included opioid-related complications during the hospital admission: pruritis, urinary retention, time to extubation, ICU length of stay, hospital length of stay, postoperative nausea and vomiting, naloxone administration, reintubation, and delirium (Supplemental Digital Content 1 for data sources and definitions, https://links.lww.com/ALN/D685). The patients were categorized into four groups (data-driven) based on intraoperative administration of intravenous methadone: no methadone, methadone dosage of less than 0.25 mg/kg, methadone dosage of 0.25 to 0.30 mg/kg, and methadone dosage of greater than 0.30 mg/kg, using the total body weight and the methadone dose administered.

All aspects of perioperative management were at the discretion of the attending physicians (e.g., anesthesiologist, intensivist, surgeon), but management was based largely on institutional protocols, which strongly emphasize multimodal analgesia and enhanced patient recovery.  Covariates were included in the regression models based on their relationship with postoperative pain: age, body mass index, sex, year of surgery, Charlson Comorbidity Index, smoking status, history of chronic pain, diagnosis of fibromyalgia, use of home opioid within 90 days of surgery, administration of antiemetics and nonopioid analgesics preoperatively and intraoperatively, preoperative or intraoperative regional block, use of local anesthetic by the surgical team, length of surgery, and surgery type (table 1).  Differences in daily pain scores and oral morphine equivalents by methadone group were assessed with covariate adjusted mixed quantile regression models with random intercepts for patients. Differences within each day were assessed via group by day interaction terms. Differences in exploratory outcomes by methadone group were assessed with quantile regression, Cox proportional hazards, and logistic regression models, adjusting for covariates using Rv4.2.1. Sensitivity analyses using ideal body weight (Devine formula) were conducted. Alpha was set at 0.0167 (0.05/3) for the primary and secondary outcomes and 0.05 for exploratory outcomes. This article adheres to the guidelines set forth by the Strengthening the Reporting of Observational Studies in Epidemiology protocol.

The mean age was 65.0 yr (interquartile range [IQR], 55.0 to 72.0), 67.4% of patients were male, the median body mass index was 28.4 kg/m² (IQR, 25.0 to 32.7), and most patients underwent isolated valve surgery (61.3%). The median operating room time was 6.4 h (IQR, 5.3 to 7.8), and regional anesthesia was utilized in 20.0% of patients. The median methadone doses were 20.0, 25.0, and 30.0 mg for the groups receiving less than 0.25 mg/kg, 0.25 to 0.30 mg/kg, and greater than 0.30 mg/kg, respectively. The median intraoperative oral morphine equivalents by group was 150, 120, 144, and 150 for the groups given no methadone, less than 0.25 mg/kg, 0.25 to 0.30 mg/kg, and greater than 0.30 mg/kg, respectively. The median time to first intraoperative methadone administration was 62 min (IQR, 34 to 78), the median number of methadone doses was 3 (IQR, 2 to 4), and the time to first intraoperative opioid administration was 11 min (IQR, 7 to 17). The methadone groups had statistically significant lower postoperative pain scores compared to the no-methadone group until postoperative day 7, favoring lower pain scores with increasing methadone dose, for days 0 and 1 (table 1). The differences between the groups narrowed over time; by postoperative day 7, the median pain score for the greater than 0.3 mg/kg group was 0.1 lower (95% CI, −0.2 to 0.0), 0.2 lower in the 0.25 to 0.3 mg/kg group (95% CI, −0.3 to −0.1), and 0.2 lower in the less than 0.25 mg/kg group compared to the no-methadone group (95% CI, −0.3 to −0.1). There was a dose–response relationship with time to first postoperative opioid administration. Postoperative oral morphine equivalents followed a dose–response relationship for all days up until postoperative day 4, with statistically significant lower postoperative oral morphine equivalents requirement for the methadone groups compared to the no-methadone group except for the less than 0.25 mg/kg group on postoperative day 3 (fig. 1). There were no differences in pruritis, urinary retention, or reintubation by methadone group; i.e., patients receiving methadone were no more likely to experience these adverse events. However, time to extubation and hospital length of stay were longer in the higher-methadone-dose groups. There were also higher odds of PONV and delirium in the greater than 0.30 mg/kg group compared to the no-methadone group. There were higher odds of postoperative naloxone and delirium for the 0.25 to 0.30 mg/kg group compared to the no-methadone group. Sensitivity analyses using ideal body weight were similar (Supplemental Digital Content 2, https://links.lww.com/ALN/D686).

Although the difference in pain scores may not be clinically significant (0.1 to 0.9 lower), this finding of lower pain scores alongside a reduction in oral morphine equivalents is clinically relevant, especially in the context of marginal gains.  There were several important side effects including increased PONV and delirium with higher doses of methadone. These findings highlight the importance of clinical judgement in weighing risks versus benefits and the need for careful consideration and individualized approaches in methadone dosing to ensure patient safety.  It is essential to acknowledge the limitations, the retrospective design, and the lack of randomization, which can lead to selection bias. Although there will still be biases associated with retrospective study designs despite efforts to address biases, this study provides data on the use of intraoperative methadone for cardiac surgery among a large, pragmatic sample. 

We thank Drs. Kumar and Jain¹  for their interest in our study on the association between intraoperative use of phenylephrine, compared to ephedrine, and delirium after noncardiac surgery under general anesthesia.

We appreciate the authors’ remarks emphasizing the importance of our secondary and sensitivity analyses from a clinical perspective: Drs. Kumar and Jain raise concerns about variability in provider choice of phenylephrine versus ephedrine. In our institutions as in many others, some providers may use ephedrine, and others use phenylephrine as their “weapon of choice” when treating hypotension. We have emphasized this in our secondary analysis investigating provider variability in vasopressor preference—adding the primary anesthesia provider as a random effect in a mixed-effects logistic regression model did not alter the primary findings. To further characterize provider variability, we have now used random-effect variances and model residuals to calculate intraclass correlation. This measure quantifies variability in the use of ephedrine versus phenylephrine that may be attributed to preference of the individual provider. Intraclass correlation demonstrated that in our model, anesthesia providers accounted for an additional 11.5% (95% CI, 10.4 to 12.8%) of the total variance in using ephedrine versus phenylephrine.

Second, Drs. Kumar and Jain note that while both drugs are typically administered as bolus, phenylephrine, as opposed to ephedrine, may also be given as an infusion. In addition, the authors write that based on a previously reported dose potency ratio of 81:1 in patients undergoing elective cesarean delivery under spinal anesthesia and given the observed doses of phenylephrine and ephedrine in our study, much higher equivalent doses of vasopressors were required in patients receiving phenylephrine, potentially introducing bias due to a higher degree of hypotension requiring treatment. This notion emphasizes the importance of our sensitivity analysis excluding patients who received doses of phenylephrine that are in line with an infusion, which confirmed the robustness of our primary analyses. In addition, when given as a bolus, the duration of action of ephedrine is three times as long as that of phenylephrine and higher equivalent doses in the phenylephrine group may further be explained by more required repetitive doses due to a shorter duration of action. We would like to emphasize that blood pressure levels, as shown in figure 2 of the article, were actually slightly higher among patients receiving phenylephrine than in those receiving ephedrine. While the notion stated by Drs. Kumar and Jain that ephedrine itself may cause delirium and psychosis is indeed provocative, it is important to note that the cited article does not contain information as to whether this may occur at clinically relevant doses rather than at high-dose intoxication. 

Most importantly, as elaborated by Dr. Gaskell et al. in their accompanying editorial discussed with Dr. Lam in an associated podcast, and stated in our conclusions, we agree with the authors that our study provides a strong justification for a randomized controlled trial as basis for treatment recommendations. In the meantime, our findings argue for careful consideration of vasopressor choice depending on specific clinical context and patient characteristics.