Objective: Our goal was to characterize a large group of children presenting to the emergency department (ED) with acute anaphylaxis, treated with intramuscular epinephrine (IM EPI) and a corticosteroid (CS), and to determine the impact of pharmacologic intervention on the rate and timing of biphasic reactions (BPR).

Methods: We reviewed consecutive children diagnosed with acute anaphylaxis managed in three EDs during a six-year period. All received IM EPI and CS, followed by monitoring for 4–6 hours post-treatment. We analyzed the rate and timing of BPR, comparing the intervals of 0–4vs4–48 hours after initiating therapy.

Results: During the study period, there were 371 cases of anaphylaxis, of which 357 (94%) received both IM EPI and CS. Of these, 49 (14%) manifested BPR [84% had received prehospital IM EPI] requiring at least one additional dose of IM EPI [14% required ≥2 additional doses]. All BPR episodes occurred within the 0–4 hour interval after initiating therapy, whereas no patient manifested a BPR requiring an additional dose of IM EPI during the 4–48 hours after initiating therapy (P =<0.001, 95% CI 0–1.3%). No patient returned to the ED with recurrence of anaphylaxis symptoms within 48 hours after discharge.

Conclusion: Approximately 1 in 7 children with anaphylaxis experience a biphasic reaction after receiving intramuscular epinephrine. Children with anaphylaxis who exhibit symptomatic resolution four hours following initiation of therapy have a low risk for subsequently developing BPR. Most BPR cases required only one additional dose of IM EPI to effect resolution. The rate of BPR in those receiving IM EPI and a corticosteroid is significantly lower >4 hours vs <4 hours after initiating therapy.

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.