Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate.

Itch of peripheral origin requires information transfer from the spinal cord to the brain for perception. Here, primate spinothalamic tract (STT) neurons from lumbar spinal cord were functionally characterized by in vivo electrophysiology to determine the role of these cells in the transmission of pruriceptive information. One hundred eleven STT neurons were identified by antidromic stimulation and then recorded while histamine and cowhage (a nonhistaminergic pruritogen) were sequentially applied to the cutaneous receptive field of each cell. Twenty percent of STT neurons responded to histamine, 13% responded to cowhage, and 2% responded to both. All pruriceptive STT neurons were mechanically sensitive and additionally responded to heat, intradermal capsaicin, or both. STT neurons located in the superficial dorsal horn responded with greater discharge and longer duration to pruritogens than STT neurons located in the deep dorsal horn. Pruriceptive STT neurons discharged in a bursting pattern in response to the activating pruritogen and to capsaicin. Microantidromic mapping was used to determine the zone of termination for pruriceptive STT axons within the thalamus. Axons from histamine-responsive and cowhage-responsive STT neurons terminated in several thalamic nuclei including the ventral posterior lateral, ventral posterior inferior, and posterior nuclei. Axons from cowhage-responsive neurons were additionally found to terminate in the suprageniculate and medial geniculate nuclei. Histamine-responsive STT neurons were sensitized to gentle stroking of the receptive field after the response to histamine, suggesting a spinal mechanism for alloknesis. The results show that pruriceptive information is encoded by polymodal STT neurons in histaminergic or nonhistaminergic pathways and transmitted to the ventrobasal complex and posterior thalamus in primates.

Response characterstics of spinothalamic tract neurons that project to the posterior thalamus in rats.

A sizeable number of spinothalamic tract axons terminate in the posterior thalamus. The functional roles and precise areas of termination of these axons have been a subject of recent controversy. The goals of this study were to identify spinothalamic tract neurons (STT) within the cervical enlargement that project to this area, characterize their responses to mechanical and thermal stimulation of their receptive fields, and use microantidromic tracking methods to determine the nuclei in which their axons terminate. Forty-seven neurons were antidromically activated using low-amplitude (< or =30 microA) current pulses in the contralateral posterior thalamus. The 51 points at which antidromic activation thresholds were lowest were surrounded by ineffective tracks indicating that the surrounded axons terminated within the posterior thalamus. The areas of termination were located primarily in the posterior triangular, medial geniculate, posterior and posterior intralaminar, and suprageniculate nuclei. Recording points were located in the superficial and deep dorsal horn. The mean antidromic conduction velocity was 6.4 m/s, a conduction velocity slower than that of other projections to the thalamus or hypothalamus in rats. Cutaneous receptive fields appeared to be smaller than those of neurons projecting to other areas of the thalamus or to the hypothalamus. Each of the examined neurons responded exclusively or preferentially to noxious stimuli. These findings indicate that the STT carries nociceptive information to several target nuclei within the posterior thalamus. We discuss the evidence that this projection provides nociceptive information that plays an important role in fear conditioning.

Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli.

We investigated the role of mechanosensitive spinothalamic tract (STT) neurons in mediating 1) the itch evoked by intradermal injection of histamine, 2) the enhanced sense of itch evoked by innocuous stroking (alloknesis), and 3) the enhanced pain evoked by punctate stimulation (hyperalgesia) of the skin surrounding the injection site. Responses to intradermal injections of histamine and capsaicin were compared in STT neurons recorded in either the superficial or the deep dorsal horn of the anesthetized monkey. Each neuron was identified by antidromic activation from the ventral posterior lateral nucleus of thalamus and classified by its initial responses to mechanical stimuli as wide dynamic range (WDR) or high-threshold (HT). Approximately half of the WDRs and one of the HTs responded weakly to histamine, some with a duration > 5 min, the maximal time allotted. WDRs but not HTs exhibited a significant increase in response to punctate stimulation after histamine consistent with their possible role in mediating histamine-induced hyperalgesia. Neither type of neuron exhibited significant changes in response to stroking, consistent with their unlikely role in mediating alloknesis. Furthermore, nearly all STT neurons exhibited vigorous and persistent responses to capsaicin, after which they became sensitized to stroking and to punctate stimulation. We conclude that the STT neurons in our sample are more likely to contribute to pain, allodynia, and hyperalgesia than to itch and alloknesis.

Responses of spinohypothalamic tract neurons in the thoracic spinal cord of rats to somatic stimuli and to graded distention of the bile duct.

Anatomical studies indicate that a relatively large percentage of spinohypothalamic tract (SHT) neurons are located within thoracic spinal segments. The aim of this study was to characterize the responses of SHT neurons in these segments of rats to innocuous and noxious stimulation of the skin and of a visceral structure, the bile duct. In addition, we attempted to determine the trajectories of the axons of the examined neurons within the diencephalon and brainstem. Fifty-three SHT neurons were recorded within segments T8-T13 in urethane anesthetized rats. Each cell was antidromically activated using current pulses < or = 30 microA delivered from the tip of an electrode located within the contralateral hypothalamus. The recording points were located in the superficial dorsal horn (9) and deep dorsal horn (44). All examined SHT neurons had receptive fields on the posterior thorax and anterior and ventral abdomen of the ipsilateral side. Ninety percent of the 41 SHT neurons responded exclusively (13) or preferentially (24) to noxious cutaneous stimuli. Thirteen of 27 (48%) examined units were activated by forceful distention of the bile duct. Response thresholds ranged from 30 to 40 mmHg. Responses incremented as pressures were increased to 50-80 mmHg. The axons of 22 of 28 (79%) examined SHT neurons appeared to cross the midline within the hypothalamus and terminate in the ipsilateral hypothalamus, thalamus or midbrain. The results indicate that SHT neurons in thoracic spinal cord of rats are capable of conveying somatic and visceral nociceptive information from the bile duct directly to targets at various levels of the brain bilaterally.