Rewarming Young Children After Drowning-Associated Hypothermia and Out-of-Hospital Cardiac Arrest: Analysis Using the CAse REport Guideline.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is recommended in adults with drowning-associated hypothermia and out-of-hospital cardiac arrest (OHCA). Our experience of managing a drowned 2-year-old girl with hypothermia (23°C) and cardiac arrest (58 min) prompted this summary using the CAse REport (CARE) guideline to address the question of optimal rewarming procedure in such patients. DESIGN/PATIENTS: Following the CARE guideline, we identified 24 reports in the "PubMed database" describing children less than or equal to 6 years old with a temperature less than or equal to 28°C who had been rewarmed using conventional intensive care ± ECMO. Adding our patient, we were able to analyze a total of 57 cases. MAIN RESULTS: The two groups (ECMO vs non-ECMO) differed with respect to submersion time, pH and potassium but not age, temperature or duration of cardiac arrest. However, 44 of 44 in the ECMO group were pulseless on arrival versus eight of 13 in the non-ECMO group. Regarding survival, 12 of 13 children (92%) undergoing conventional rewarming survived compared with 18 of 44 children (41%) undergoing ECMO. Among survivors, 11 of 12 children (91%) in the conventional group and 14 of 18 (77%) in the ECMO group had favorable outcome. We failed to identify any correlation between "rewarming rate" and "outcome." CONCLUSIONS: In this summary analysis, we conclude that conventional therapy should be initiated for drowned children with OHCA. However, if this therapy does not result in return of spontaneous circulation, a discussion of withdrawal of intensive care might be prudent when core temperature has reached 34°C. We suggest further work is needed using an international registry.

Life-Threatening Accidental Intravenous Epinephrine Overdose in a 12-Year-Old Boy.

Reports on accidental intravenous epinephrine overdose in children are extremely rare, although medication errors in the management of pediatric anaphylaxis seem to be frequent. We report a case of a 12-year-old boy presenting with a long-lasting skin rash and dyspnea who was incorrectly diagnosed with early anaphylactic shock and was treated with 10-fold the recommended dose administered by the wrong route (intravenous instead of intramuscular). He reacted with acute loss of consciousness and acute cardiorespiratory failure due to arterial hypotension, ischemic heart failure, and severe pulmonary edema. He responded rapidly to mechanical ventilation, treatment with diuretics, and low-dose inotropes and recovered without sequelae. Despite this ultimately favorable outcome, we report this case to remind the scientific community that inadvertent and accidental epinephrine overdosing is probably an underrecognized event, which can result in potentially lethal complications. Heightening the awareness of the personnel, implementing safety precautions for the dosage and the route of administration, stocking of prefilled intramuscular dose syringes for emergency use in anaphylaxis and, ideally, introducing a standardized drug order form should reduce potential risks and facilitate proper and optimal treatment for all acutely ill children.

An Fc-optimized NKG2D-immunoglobulin G fusion protein for induction of natural killer cell reactivity against leukemia.

Recruitment of Fc-receptor-bearing effector cells, such as natural killer (NK) cells, is a feature critical for the therapeutic success of antitumor antibodies and can be improved by the modifications of an antibody's Fc part. The various ligands of the activating immunoreceptor NKG2D, NKG2DL) are selectively expressed on malignant cells including leukemia. We here took advantage of the tumor-associated expression of NKG2DL for targeting leukemic cells by NKG2D-immunoglobulin G (IgG)1 fusion proteins containing modified Fc parts. Compared to NKG2D-Fc containing a wild-type Fc part (NKG2D-Fc-WT), our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. Functional analyses with allogenic as well as autologous NK cells and primary malignant cells of leukemia patients revealed that NKG2D-Fc-KO significantly reduced NK reactivity by blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT already enhanced antileukemia reactivity by inducing antibody-dependent cellular cytotoxicity (ADCC) with NKG2D-Fc-ADCC mediating significantly stronger effects. Parallel application of NKG2D-Fc-ADCC with Rituximab caused additive effects in lymphoid leukemia. In line with the tumor-associated expression of NKG2DL, no NK cell ADCC against resting healthy blood cells was induced. Thus, NKG2D-Fc-ADCC potently enhances NK antileukemia reactivity despite the inevitable reduction of activating signals upon binding to NKG2DL and may constitute an attractive means for immunotherapy of leukemia.

Impaired tumor rejection by memory CD8 T cells in mice with NKG2D dysfunction.

Cytotoxic T cells are important effectors for robust antitumor immune responses. However, tumor-infiltrating CD8 T cells are often functionally impaired. Insufficient antitumor activity of CD8 T cells can be due to a lack of costimulatory signals. NKG2D is such a costimulatory receptor on CD8 T cells that facilitates immunorecognition of stressed and malignant cells, promotes tumor rejection by NK and CD8 T cells and contributes to immunosurveillance of spontaneous malignancies. Previous reports suggested an involvement of NKG2D in establishing CD8 T cell-mediated antitumor memory. However, the significance of NKG2D for the generation and effector phase of memory CD8 T cell responses is largely unknown. To address these issues, we made use of a transgenic mouse model (H2-K(b)-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-K(b)/OVA(257-264)) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-K(b)-MICA mice. While expansion of memory T cells in these mice on antigen challenge was not different from controls, CD8 memory T cells of H2-K(b)-MICA mice did not effectively eliminate tumor cells in vivo. Altogether, our data suggest that NKG2D has no major role in the generation and expansion of memory CD8 T cells, but rather substantially enhances the cytolytic effector responses of reactivated memory T cells and thereby contributes to an efficacious tumor rejection.