Science, Medicine, and the Anesthesiologist

It has been known for a long time that music can relieve pain in humans, but the underlying neurocircuits are largely unknown. It is also unknown how animals perceive music. This murine study investigated whether different types of music or white noise differed in effect on nociception. A 5-decibel increase in sound intensity, compared with ambient sound levels, was found to be a key factor in inducing nociception. The study employed a multidisciplinary approach, including viral tracing, microendoscopic calcium imaging, and multielectrode recordings in freely moving mice to identify the neurocircuits that mediate antinociception induced by low signal-to-noise ratio sounds. Artificial activation of glutamatergic inputs from the auditory cortex to the thalamic posterior and ventral posterior nuclei was able to modulate sound-induced analgesia. The study also demonstrated the novel finding of a descending corticothalamic input from layer 5 neurons of the auditory cortex to the somatosensory thalamus.

Take home message: This study reveals the corticothalamic neurocircuits that can mediate sound-induced analgesia in mice, providing a mechanistic insight into music treatment for pain in patients.

The impact of a prior ischemic stroke on the risk of a recurrent stroke after elective surgery is uncertain. This cohort study (n = 5,841,539; mean age, 74 yr; 58% female) used Medicare Provider Data Files (2011 to 2018) to evaluate the association of prior acute ischemic stroke (1% of cohort) and the risk after elective, nonneurologic, noncardiac surgery in patients age >65 yr. Outcomes included acute ischemic stroke during the index surgical admission or rehospitalization for stroke within 30 days of surgery and 30-day all-cause mortality. Patients with a stroke within 30 days before surgery had elevated risk of perioperative stroke (adjusted odds ratio, 8.02; 95% CI, 6.37 to 10.10; P < 0.001) compared with patients without. There was no significant difference in risk in patients with prior stroke at 61 to 90 days versus 181 to 360 days (adjusted odds ratio, 5.01; 95% CI, 4.00 to 6.29 vs. 4.76; 95% CI, 4.26 to 5.32). The risk of 30-day all-cause mortality was higher in patients undergoing surgery within 30 days of a prior stroke (adjusted odds ratio, 2.51; 95% CI, 1.99 to 3.16). Although the risk was lower at 61 to 90 days (adjusted odds ratio, 1.49; 95% CI, 1.15 to 1.92), it did not decline significantly after an interval of 360 or more days.

Take home message: This administrative observational cohort analysis confirms the elevated risk of recurrent stroke after noncardiac surgery particularly within 30 days prior and further notes that risk of all-cause mortality remains elevated for an extended period postoperatively.

Visceral hyperalgesia is a chronic pain disease in patients with irritable bowel syndrome (IBS) that has been associated with the composition of the gut microbiota. Previously, a dietary change in fermentable carbohydrates resulted in reduced pain that was associated with a change in the gut microbiota and lower concentrations of urinary histamine. Germ-free mice were colonized with human gut microbiota obtained from control patients or patients with IBS with either high or low urinary histamine levels. Mechanosensitivity of single afferent colonic nerves was higher in mice colonized with gut microbiota from humans with high urinary histamine. During periods of greater intestinal pain, patients’ fecal microbiota produced higher levels of histamine, which was associated with a specific bacterial strain, Klebsiella aerogenes, which was greater in the microbiota of patients with IBS. The excitability of dorsal root ganglion neurons isolated from pathogen-free mice was greater in the presence of colonic supernatants from patients with IBS, and this hyperexcitability was inhibited by a histamine receptor antagonist. Mast cells, which have been colocalized with colonic nerve fibers in patients with IBS, were greater in close proximity to nerves in mice colonized with gut microbiota from patients with IBS with high but not low levels of urinary histamine.

Take home message: Visceral hypersensitivity was modulated by the specific microbial composition of the gut flora and was associated with specific bacterial species producing greater histamine. Dietary therapies targeting specific gut microbiota composition, microbiota-directed therapies, or histamine receptor antagonists may be novel therapies for some patients with IBS suffering from chronic pain.

Sepsis is a life-threatening systemic response to infection that annually claims up to 11 million lives worldwide. The literature regarding intravenous vitamin C to lower sepsis-related mortality shows mixed results. This randomized, controlled trial was conducted in 35 medical-surgical intensive care units (ICUs) across Canada, France, and New Zealand, to evaluate the effect of intravenous vitamin C (50 mg/kg mixed in 5% dextrose, normal saline, or water and administered every 6 h for 96 h) versus placebo on a composite primary outcome of death or persistent organ dysfunction (defined as receipt of vasopressors, mechanical ventilation, or new renal-replacement therapy at trial day 28) among adult patients admitted to the ICU for proven or suspected infection and who required vasopressor therapy. At day 28, 45% of vitamin C group participants (n = 429; 35% female; median age 65 yr) had died or had ongoing organ dysfunction versus 39% of placebo group participants (n = 433; 40% female; median age 65 yr), with an estimated treatment effect of 1.21 (95% CI, 1.04 to 1.40) and adjusted risk ratio of 1.15 (95% CI, 0.90 to 1.47). There were no differences regarding safety outcomes (e.g., hypoglycemia), Sequential Organ Failure Assessment scores, 6-month survival, or health-related quality of life.

Take home message: Intravenous vitamin C led to higher risk of death or persistent organ dysfunction at 28 days among adults with sepsis requiring vasopressors in the intensive care unit.

Hypotension commonly occurs after tracheal intubation of critically ill adults. The role of prophylactic fluid administration before intubation is uncertain. This multicenter (11 U.S. intensive care units), pragmatic randomized clinical trial (2019 to 2021) included 1,067 critically ill adults requiring tracheal intubation involving an induction medication and either bag-mask or noninvasive ventilation before laryngoscopy. Subjects were randomized to either up to 500 ml isotonic crystalloid (n = 538; median fluid bolus, 500 ml [interquartile range, 300 to 500 ml]) or no additional fluid (n = 527). All other details of clinical care were at the discretion of the treating physician. The primary outcome was cardiovascular collapse (new or increased receipt of vasopressors or a systolic blood pressure <65 mmHg between induction of anesthesia and 2 min after tracheal intubation, or cardiac arrest or death between induction of anesthesia and 1 h after tracheal intubation). The secondary outcome was the incidence of death before day 28. A total of 1,065 patients completed the trial (median age, 62 yr; 42% female). There was no difference between groups in the primary outcome (21% fluid bolus vs. 18% no fluid bolus (absolute difference, 3% [95% CI, −2% to 8%]; P = 0.25) or the secondary outcome (41% vs. 42%, respectively).

Take home message: In this pragmatic, randomized trial of fluid administration before intubation of critically ill patients in the intensive care unit setting, prophylactic administration of isotonic crystalloid had no effect on postintubation cardiovascular instability or mortality by 28 days.

This prospective observational cohort study evaluated the association of angiotensin receptor blockers or angiotensin-converting enzyme inhibitor use and outcomes in patients hospitalized with COVID-19 with a special focus on sex-related differences. The angiotensin receptor blockers CORONA I study was performed in 10 large hospitals in Canada from February 2020 to March 2021, including 1,686 patients. Males had significantly worse outcome with greater in-hospital mortality (adjusted odds ratio, 1.46; 95% CI, 1.11 to 1.93; P = 0.008), admission to the intensive care unit (adjusted odds ratio, 1.46; 95% CI, 1.14 to 1.86; P = 0.003), use of ventilation (adjusted odds ratio, 1.54; CI, 1.20 to 1.99; P < 0.001), and use of vasopressors (adjusted odds ratio, 1.58; CI, 1.23 to 2.03; P < 0.001) compared with female patients. Females with angiotensin receptor blocker medication before admission did not show a difference in the use of ventilation (P = 0.315) and vasopressors (P = 0.771) and the time to hospital discharge (P = 0.077) compared with females without angiotensin receptor blocker medication. For males on angiotensin receptor blocker medication, there was significantly less use of ventilation (adjusted odds ratio, 0.52; CI, 0.32 to 0.83; P = 0.007), less use of vasopressors (adjusted odds ratio, 0.55; CI, 0.34 to 0.87; P = 0.011), and a shorter time to discharge (adjusted hazard ratio, 1.35; CI, 1.08 to 1.70; P = 0.009). Interactions between females and males were positive for the use of mechanical ventilation (P = 0.006) and the use of vasopressors (P = 0.044), however not for time to hospital discharge (P = 0.706). For angiotensin-converting enzyme inhibitors, outcomes were similar in males and females.

Take home message: This study underlines sex- and angiotensin receptor blocker medication-related differences in certain outcome parameters in patients with COVID-19. Mechanistically, the renin-angiotensin system pathway might play an important role for these clinical findings.

Patients with sepsis have better outcomes if they are correctly diagnosed and treated quickly. Sepsis identification may be facilitated by using artificial intelligence systems to raise alerts. In this prospective cohort study, the Targeted Real-time Early Warning System, a machine learning electronic health record–based system developed over a 3-yr period was used to raise sepsis alerts before antibiotic initiation in 6,877 patients after deployment over a 2-yr study period at two academic and three community hospitals in the United States. In 4,220 patients, the alert was evaluated and confirmed within 3 h, compared with 2,657 in which the alert was not confirmed within 3 h. Timely confirmation of sepsis resulted in an 18% adjusted relative reduction in mortality (95% CI, −26.31 to −9.65%; P < 0.001), a 26% reduction in organ failure progression (95% CI, −0.4 to −0.11; P = 0.001), and 11.6 h shorter hospital length of stay among survivors (95% CI, −18.13 to −5.03; P = 0.001). The beneficial effects were greatest in the prespecified high-risk subgroup. There was an 8% increase in hospital mortality per hour of delay in antibiotic administration (95% CI, 1.02 to 1.15).

Take home message: Deployment of a machine learning–based Targeted Real-time Early Warning System in five hospitals was associated with clinically and statistically significant improvement in outcomes in patients with sepsis in whom the alert was evaluated and confirmed within 3 h relative to those with longer times.

Intravenous fluid administration is a central component in the management of septic shock, although the volume of fluid required remains controversial. In this multicenter (31 European intensive care units) open-label trial, patients with septic shock who had received at least 1 l of fluid in the 24 h prior were randomized to either a restricted or a standard fluid protocol. In the restrictive group, an intravenous bolus of 250 to 500 ml isotonic crystalloid was allowed in the presence of hyperlactatemia, mottling beyond the edge of the kneecap, hypotension, or decreased urine output. In the standard group, an intravenous bolus of isotonic crystalloid (without upper volume limit) was given if the patient had improvement in hemodynamic factors per the 2016 Surviving Sepsis Campaign guidelines. The primary outcome was death from any cause within 90 days after randomization. A total of 770 patients were assigned to the restrictive group and 784 to the standard group. The restrictive group received a median of 1,798 ml (500 to 4,366 ml) versus 3,811 ml (1,861 to 6,762) standard. At 90 days, death had occurred in 42.3% of the patients in the restrictive group versus 42.1% in the standard group (P = 0.96). No difference in serious adverse events was observed.

Take home message: In adult patients with septic shock, intravenous fluid restriction did not result in fewer deaths at 90 days when compared to standard guideline directed fluid therapy.

The optimal dose of tranexamic acid to reduce bleeding and transfusion without increasing the risk of adverse effects in patients undergoing cardiac surgery remains to be determined. This multicenter (four Chinese centers) study prospectively randomized adult patients undergoing cardiac surgery with cardiopulmonary bypass to high-dose (30 mg/kg bolus, 16 mg · kg^–1 · h^–1, and 2 mg/kg prime) (n = 1,525) versus low-dose (10 mg/kg bolus, 2 mg · kg^–1 · h^–1, and 1 mg/kg prime) (n = 1,506) tranexamic acid. The primary clinical benefit outcome was the rate of perioperative allogeneic red blood cell transfusion (superiority hypothesis), and the primary safety outcome was a composite of the 30-day postoperative rate of mortality, seizure, kidney dysfunction, and thrombotic events (noninferiority hypothesis with a margin of 5%). Red blood cell transfusion occurred in 22% in the high-dose group versus 26% in the low-dose group (risk difference, −4% [one-sided 97.55% CI, −∞ to −1.1%], relative risk, 0.84 [one-sided 97.55% CI, −∞ to 0.96; P = 0.004]). The composite safety endpoint occurred in 18% versus 17% of patients respectively (risk difference, 0.8%; one-sided 97.55% CI, −∞ to 3.9%; P = 0.003 for noninferiority). No significant differences between groups in thrombotic complications or seizures were reported.

Take home message: In this randomized study, administration of high-dose tranexamic acid resulted in a modest reduction in the proportion of patients receiving allogeneic red blood cell transfusion without greater adverse effects.

Patients with reduced neutrophil counts (including congenital neutropenia) as well as those on cytotoxic or immunosuppressive medications are at high risk of opportunistic fungal infections with significant mortality. Expanding a patient’s neutrophil count to prevent fungal infections is complicated by the lack of protocols for adequate cell preservation and a short lifespan of donor neutrophils. To investigate these issues, a neutrophil progenitor cell line was created by conditional immortalization in a neutropenic mouse model. This was achieved by exploiting the ability of a member of the homeobox family of transcription factors (Hoxb8) to keep hematopoietic progenitors in the undifferentiated state with self-renewal capacity, and by transducing the cells with an estrogen receptor-Hoxb8 fusion protein allowing for unlimited ex vivo expansion in the presence of estrogen and maturation into fully differentiated neutrophils upon hormone withdrawal. In a sterile peritoneal challenge model, these cells were able to home to the bone marrow and spleen, and to respond to inflammatory stimuli. Transfused cells administered as prophylactic therapy or treatment against disseminated Candida albicans or as treatment against pulmonary Aspergillus fumigatus were capable of successfully increasing the survival in irradiated mice after experimental fungal infections.

Take home message: These murine data support future investigation of genetically engineered progenitor-based cellular therapies for the treatment of fungal infections in high-risk neutropenic patients.

The impact on patient outcomes of anesthesiologists’ overlapping clinical responsibilities supervising care providers in different operating rooms has not been systematically evaluated. Using the Multicenter Perioperative Outcomes Group electronic health record registry, surgical patient morbidity and mortality was determined stratified by anesthesiologist staffing ratios. This retrospective, matched cohort study included records of 578,815 patients aged older than 18 y undergoing major inpatient surgery in 23 U.S. academic and private hospitals. Four balanced groups of anesthesiologist staffing ratios (one, two, three, or four overlapping operations) were created using propensity score–matching controlling for patient-, operative-, and hospital-level confounders. The primary composite outcome was 30-day mortality and six major adverse outcomes (cardiac, respiratory, gastrointestinal, urinary, bleeding, and infectious complications). Patients in group 2-3 compared to group 1-2 had a 4% relative greater risk-adjusted mortality and morbidity (5.06% vs. 5.25%; adjusted odds ratio, 1.04; 95% CI, 1.01 to 1.08; P = 0.02) and those in group 3-4 had a 14% greater risk-adjusted mortality and morbidity (5.06% vs. 5.75%; adjusted odds ratio, 1.15; 95% CI, 1.09 to 1.21; P < 0.001).

Take home message: This large, retrospective, multicenter, observational cohort analysis reports greater surgical patient morbidity and mortality when anesthesiologists supervise three to four overlapping operations in a care team model compared with supervising one to two operations.