Early diagnosis of haemorrhagic shock (HS) might be difficult because of compensatory mechanisms. Clinical scoring systems aimed at predicting transfusion needs might assist in early identification of patients with HS. The Shock Index (SI) - defined as heart rate divided by systolic BP - has been proposed as a simple tool to identify patients with HS. This systematic review discusses the SI's utility post-trauma in predicting critical bleeding (CB). We searched the databases MEDLINE, Embase, CINAHL, Cochrane Library, Scopus and PubMed from their commencement to 1 September 2013. Studies that described an association with SI and CB, defined as at least 4 units of packed red blood cells (pRBC) or whole blood within 24 h, were included. Of the 351 located articles identified by the initial search strategy, five met inclusion criteria. One study pertained to the pre-hospital setting, one to the military, two to the in-hospital setting, and one included analysis of both pre-hospital and in-hospital values. The majority of papers assessed predictive properties of the SI in ≥10 units pRBC in the first 24 h. The most frequently suggested optimal SI cut-off was ≥0.9. An association between higher SI and bleeding was demonstrated in all studies. The SI is a readily available tool and may be useful in predicting CB on arrival to hospital. The evaluation of improved utility of the SI by performing and recording at earlier time-points, including the pre-hospital phase, is indicated.

Author contributionsML, NJ, PJN, and LEB designed and carried out experiments, performed data analyses, and drafted the manuscript. B Rollo, S Pachernegg, A Sedo, and JH performed qPCR experiments and analyses. KR and A Sedo performed immunohistochemistry experiments and analyses. LD and LJ performed behavioral experiments and analyses. TB and B Roberts performed mass spectrometry experiments and analyses. A Soriano, AN, KD, SM, CAR, FR, and S Petrou designed and coordinated the study. All authors read and contributed to the revision of manuscript.

The clinical spectrum associated with SCN2A de novo mutations (DNMs) continues to expand and includes autism spectrum disorder with or without seizures, in addition to early and late seizure onset developmental and epileptic encephalopathies (DEEs). Recent biophysical studies on SCN2A variants suggest that the majority of early seizure onset DEE DNMs cause gain of function. Gain of function in SCN2A, the principal sodium channel of excitatory pyramidal neurons, would result in heightened neuronal activity and is likely to underlie the pathology seen in early seizure onset DEE patients. Supratherapeutic dosing of the non-selective sodium channel blocker phenytoin, is effective in controlling seizures in these patients but does not impact neurodevelopment, raising the idea that more profound and specific reduction in SCN2A function could significantly improve clinical outcome. To test the potential therapeutic benefit of reducing SCN2A in early seizure onset DEE we centrally administered an antisense oligonucleotide (ASO) targeting mouse Scn2a (Scn2a ASO) to a mouse model of human SCN2A early seizure onset DEE. Mice were genetically engineered to harbour the human equivalent SCN2A p.R1882Q mutation (Q/+), one of the most recurrent mutations in early seizure onset DEE. Q/+ mice presented with spontaneous seizures at postnatal day (P) 1 and did not survive beyond P30. Intracerebroventricular Scn2a ASO administration into Q/+ mice between P1-2 (that reduced Scn2a mRNA levels by 50%) significantly extended lifespan and markedly reduced spontaneous seizures occurrence. Across a range of cognitive and motor behavioural tests, Scn2a ASO treated Q/+ mice were largely indistinguishable from wildtype (+/+) mice. Further improvements in survival and behaviour were seen by adjustment of dosing regimens during development. Scn2a ASO efficacy was also evident at the cellular level. Whole cell patch clamp recording showed that Scn2a ASO administration reversed changes in neuronal excitability in layer 2/3 pyramidal neurons of Q/+ mice to levels seen in +/+ mice. Safety was assessed in +/+ mice and showed a developmental stage dependent tolerability and a favourable therapeutic index. This study suggests that a human SCN2A gapmer ASO could profoundly and safely impact early seizure onset DEE patients and heralds a new era of precision therapy in neurodevelopmental disorders.