Daily Anesthesiology Research Analysis
Analyzed 67 papers and selected 3 impactful papers.
Summary
Structural work reveals ketamine directly binds and activates human opioid receptors, reframing its analgesic mechanisms. A large entropy-balanced cohort questions benefits of pulmonary artery catheters in cardiac surgery, while a pragmatic RCT shows low-dose intrathecal morphine outperforms intrathecal fentanyl for post-cesarean analgesia in a resource-limited setting.
Research Themes
- Mechanisms of anesthetic and analgesic action
- Value and consequences of invasive perioperative monitoring
- Optimizing obstetric anesthesia analgesia in resource-limited settings
Selected Articles
1. Structural basis of opioid receptor activation by PCP and ketamine.
Using structural biology with complementary mutagenesis and SAR, the authors show ketamine and PCP directly bind and activate human opioid receptors, and report the apo structure of the human κ-opioid receptor. Distinct binding dynamics for ketamine versus PCP at the orthosteric site provide a mechanistic basis for ketamine’s unique pharmacology beyond NMDAR antagonism.
Impact: This work reframes ketamine’s mechanism by implicating direct opioid receptor activation, a paradigm-relevant finding for anesthesia, analgesia, and addiction science.
Clinical Implications: Understanding ketamine’s opioid receptor engagement may inform perioperative dosing strategies, predict naloxone responsiveness, and guide the development of safer, biased ligands for analgesia.
Key Findings
- Cryo-EM structures show ketamine and PCP directly bind and activate human opioid receptors.
- Site-directed mutagenesis and SAR pinpoint key recognition motifs modulating efficacy.
- Ligand-free (apo) human κ-opioid receptor structure reveals pre-engagement conformational details.
- Ketamine exhibits distinct orthosteric binding dynamics versus PCP, potentially explaining unique pharmacology.
Methodological Strengths
- Integration of high-resolution structural biology with mutagenesis and SAR
- Cross-receptor analysis including apo κ-opioid receptor state
Limitations
- Findings are preclinical; no direct in vivo confirmation of receptor-mediated clinical effects
- Behavioral/clinical correlates of receptor engagement were not assessed
Future Directions: Quantify opioid receptor contributions to ketamine’s analgesia and antidepressant effects in vivo; develop ligands leveraging identified motifs for safer, biased signaling; evaluate naloxone modulation in clinical trials.
Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine's dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure-activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine's versatility in clinical settings.
2. Low-dose intrathecal morphine versus intrathecal fentanyl for post-caesarean analgesia in a resource-constrained setting: a pragmatic randomised trial.
In a blinded, pragmatic randomized trial at a public-sector hospital, both 50 µg and 100 µg intrathecal morphine reduced 24-hour IV PCA morphine consumption compared with 25 µg intrathecal fentanyl, with no difference between morphine doses. Pain scores and perceived pain relief were similar across groups.
Impact: Provides pragmatic, dose-efficient evidence supporting low-dose intrathecal morphine, including 50 µg, as an implementable strategy in resource-limited obstetric anesthesia.
Clinical Implications: Consider adopting 50 µg intrathecal morphine for cesarean analgesia to reduce systemic opioid needs without compromising pain control, particularly where monitoring resources are limited.
Key Findings
- Median 24-hour IV PCA morphine was lower with intrathecal morphine 100 µg (12.5 mg) and 50 µg (15.0 mg) versus intrathecal fentanyl 25 µg (26.0 mg).
- No significant difference between 50 µg and 100 µg intrathecal morphine in the primary endpoint after adjustment.
- Pain scores at rest and with cough, and perceived pain relief, were similar across groups.
Methodological Strengths
- Participant- and assessor-blinded, parallel-group randomized design
- Pragmatic setting with standardized multimodal analgesia and supportive ITT analysis
Limitations
- Single-center with modest sample size; not powered for rare adverse events
- Outcomes focused on opioid consumption; limited assessment of side effects (e.g., pruritus, respiratory depression)
Future Directions: Multicenter trials to confirm effectiveness and safety profiles (including pruritus, PONV, respiratory depression), cost-effectiveness analyses, and implementation studies in diverse resource settings.
BACKGROUND: Intrathecal morphine is recommended for post-caesarean analgesia, but its implementation remains inconsistent in resource-constrained obstetric services, where short-acting intrathecal fentanyl is often favoured instead because of familiarity and perceived simplicity of use. We compared two low doses of intrathecal morphine with intrathecal fentanyl in women undergoing caesarean delivery under spinal anaesthesia in a South African public-sector hospital. METHODS: This was a single-centre, participant- and outcome-assessor-blinded, parallel-group pragmatic randomised trial. Women undergoing caesarean delivery under single-shot spinal anaesthesia were allocated to hyperbaric bupivacaine 0.5% 1.8 ml mixed with intrathecal morphine 100 µg (M100), intrathecal morphine 50 µg (M50), or intrathecal fentanyl 25 µg (F25). All participants received postoperative intravenous (IV) morphine patient-controlled analgesia (PCA) and rectal indomethacin. The primary outcome was cumulative 24-hour IV PCA morphine consumption. Secondary outcomes were morphine consumption for 0-12 h and 12-24 h, pain numerical rating scale (NRS) scores at rest and with cough at 12 and 24 h, perceived pain relief over 24 h, and whether participants wanted more analgesic treatment. The prespecified primary analysis was per protocol, with a supportive intention-to-treat analysis. RESULTS: One hundred women were randomised. Ninety-three comprised the per-protocol efficacy cohort (M100 n = 32, M50 n = 29, F25 n = 32). Median 24-hour IV PCA morphine consumption differed significantly between groups: 12.5 mg (Q1, Q3: 6.0, 20.25) in M100, 15.0 mg (9.0, 25.0) in M50, and 26.0 mg (16.5, 38.5) in F25 (p < 0.001). After Holm adjustment for the three pairwise comparisons at the primary endpoint, the morphine groups required less rescue opioid than F25 (M100 vs. F25 adjusted p = 0.00081; M50 vs. F25 adjusted p = 0.019), whereas M100 and M50 did not differ (adjusted p = 0.326). Hodges-Lehmann estimates of the median difference in 24-hour morphine consumption were - 13.0 mg (95% CI -20.0 to -7.0) for M100 vs. F25 and - 10.5 mg (95% CI -18.0 to -3.0) for M50 vs. F25, and - 3.0 mg (95% CI -8.0 to 3.0) for M100 vs. M50. The same directional pattern was present for 0-12 h and 12-24 h. Pain scores at rest and with cough did not differ significantly between groups at either postoperative assessment. Perceived pain relief over 24 h was similar across groups, and the proportion of women who wanted more analgesic treatment did not differ significantly. The intention-to-treat analysis was concordant with the per-protocol analysis. CONCLUSIONS: In this single-centre pragmatic trial conducted in a South African public-sector hospital, low-dose intrathecal morphine at both 50 µg and 100 µg reduced 24-hour postoperative opioid requirements after caesarean delivery compared with intrathecal fentanyl 25 µg. These findings additionally support 50 µg intrathecal morphine as an effective and implementable option for post-caesarean analgesia in resource-constrained obstetric settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02577809 (retrospectively registered 10 October 2015).
3. Associations Between Pulmonary Artery Catheter Use and Outcomes After Cardiac Surgery: An Entropy-Balanced Cohort Study.
Among 10,044 cardiac surgery patients, pulmonary artery catheter use was not associated with 90-day or in-hospital mortality after entropy balancing, but was linked to longer ICU stays, higher AKI incidence, and greater treatment intensity (vasopressors, inotropes, fluids, transfusion, ventilation duration).
Impact: Challenges routine use of pulmonary artery catheters in cardiac anesthesia by demonstrating no mortality benefit and potential harm signals, using robust causal balancing.
Clinical Implications: Selective, indication-driven PAC use should be considered; teams should weigh potential renal and ICU resource impacts against benefits and consider less invasive monitoring strategies.
Key Findings
- No association between PAC use and 90-day mortality (RR 0.966; p=0.816) or in-hospital mortality.
- PAC use associated with longer ICU length of stay (MD 13.1 hours; p<0.001) and increased AKI (RR 1.12; p<0.001).
- Higher treatment intensity with PACs: more vasopressors/inotropes, higher positive fluid balance, greater transfused RBC volume, longer ventilation, and more postoperative organ dysfunction time.
Methodological Strengths
- Large sample size with entropy balancing achieving exact covariate balance
- Comprehensive assessment of clinical and mechanistic outcomes
Limitations
- Retrospective single-center design with potential residual confounding
- Device use may proxy for unmeasured severity or clinician preference (confounding by indication)
Future Directions: Prospective, multicenter pragmatic trials or quasi-experiments to define PAC indications and targets; subgroup analyses to identify patients who may benefit; evaluation of de-implementation strategies.
BACKGROUND: Pulmonary artery catheters are used widely in cardiac surgery despite conflicting associations with patient outcomes. We evaluated the associations between pulmonary artery catheter use and clinical outcomes following cardiac surgery using a large cohort of patients treated at a US academic center. METHODS: We performed a retrospective entropy-balanced cohort study of consecutive adults undergoing cardiac surgery from a single tertiary center in Boston, Massachusetts, from 2008 to 2022. We used entropy balancing to achieve exact covariate balance on prespecified baseline characteristics and then estimated the average treatment effect of pulmonary artery catheter use on clinical and mechanistic outcomes. The primary outcome was mortality measured 90 days after surgery. Secondary outcomes were acute kidney injury, hospital and intensive care unit (ICU) length of stay, time in postoperative organ dysfunction measured at 7 days, prolonged inotrope use (>4 hours), significant peak vasopressor requirement (>0.1 μg/kg/min in norepinephrine equivalents), net fluid balance at 24 hours, number of fluid boluses administered, volume of allogeneic red blood cells transfused, and total duration of mechanical ventilation. RESULTS: We included 10,044 patients, of whom 5850 (58.2%) were managed with a pulmonary artery catheter. Pulmonary artery catheter use was not associated with 90-day mortality (risk ratio [RR], 0.966; 95% confidence interval [CI], 0.719-1.30; P =.816) nor in-hospital mortality (RR, 0.921; 95% CI, 0.632-1.34; P =.670). There was no between-group difference in hospital length of stay (median difference [MD], 0.050 days; 95% CI, 0.0477-0.148; P =.269), but patients managed with a pulmonary artery catheter had greater ICU length of stay (MD = 13.1 hours; 95% CI, 9.74-16.4; P <.001). Pulmonary artery catheters were also associated with increased incidence of acute kidney injury (RR, 1.12; 95% CI, 1.07-1.17; P <.001). Patients who received a pulmonary artery catheter were more likely to have prolonged inotrope requirements (RR, 4.13; 95% CI, 3.42-4.98; P <.001), significant vasopressor requirements (RR, 1.37; 95% CI, 1.28-1.46; P <.001), higher positive fluid balances (MD, 566 mL; 95% CI, 453-678; P <.001), higher volumes of allogeneic RBCs transfused (MD, 226 mL; 95% CI, 183-269; P <.001), higher time in postoperative organ dysfunction (MD, 3.96 hours; 95% CI, 3.01-4.90; P <.001), and longer durations of mechanical ventilation (MD, 11.3 hours; 95% CI, 7.33-15.2; P <.001). CONCLUSIONS: In a large entropy-balanced cohort study of adults undergoing cardiac surgery, pulmonary artery catheter use was not associated with mortality, but was linked with a higher treatment intensity and longer ICU stay.