C. C. Armsby

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca2+-activated K+ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K+ and water loss via this channel could be a potential therapy in vivo. We treated five subjects who have sickle cell anemia with oral clotrimazole, a specific Gardos channel inhibitor. Patients were started on a dose of 10 mg clotrimazole/kg/d for one week. Protocol design allowed the daily dose to be escalated by 10 mg/kg each week until significant changes in erythrocyte density and K+ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K+ transport. At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K+ content, and somewhat increased hemoglobin levels. Adverse effects were limited to mild/moderate dysuria in all subjects, and a reversible increase in plasma alanine transaminase and aspartic transaminase levels in two subjects treated with 30 mg clotrimazole/kg/d. This is the first in vivo evidence that the Gardos channel causes dehydration of sickle erythrocytes, and that its pharmacologic inhibition provides a realistic antisickling strategy.

Use of high-flow nasal cannula support in the emergency department reduces the need for intubation in pediatric acute respiratory insufficiency

Objectives The objective of this study was to determine whether the use of heated, humidified, high-flow nasal cannula (HFNC) therapy is associated with a decreased need for intubation in patients presenting to a pediatric emergency department (PED) and admitted to a pediatric intensive care unit (PICU) with acute respiratory insufficiency (ARI). Methods A retrospective study of all patients admitted from the PED to the PICU with ARI from January 2006 through December 2009. Patients admitted before the availability of HFNC (cohort 1) were compared with those admitted after the availability of HFNC but before implementation of an institution-wide guideline on pediatric HFNC usage (cohort 2) and those admitted after the implementation of a pediatric HFNC usage guideline (cohort 3). Results After controlling for age, month of admission, type of respiratory illness, and severity of illness, there was an 83% reduction in the odds of intubation in the PED in cohort 3 compared with cohort 1 (odds ratio, 0.17; 95% confidence interval, 0.06-0.50; P = 0.001). There was no significant change in mortality or median PICU length of stay after the introduction of HFNC. Conclusions High-flow nasal cannula used early in the development of pediatric ARI is associated with a decreased the need for intubation and mechanical ventilation.

Ca2+-activated K+ channels of human and rabbit erythrocytes display distinctive patterns of inhibition by venom peptide toxins

Despite recent progress in the molecular characterization of high-conductance Ca2+-activated K+ (maxi-K) channels, the molecular identities of intermediate conductance Ca2+-activated K+ channels, including that of mature erythrocytes, remains unknown. We have used various peptide toxins to characterize the intermediate conductance Ca2+-activated K+ channels (Gardos pathway) of human and rabbit red cells. With studies on K+ transport and on binding of 125I-charybdotoxin (ChTX) and 125I-kaliotoxin (KTX) binding in red cells, we provide evidence for the distinct nature of the red cell Gardos channel among described Ca2+-activated K+ channels based on (i) the characteristic inhibition and binding patterns produced by ChTX analogues, iberiotoxin (IbTX) and IbTX-like ChTX mutants, and KTX (1–37 and 1–38 variants); (ii) the presence of some properties heretofore attributed only to voltage-gated channels, including inhibition of K transport by margatoxin (MgTX) and by stichodactyla toxin (StK); (iii) and the ability of scyllatoxin (ScyTX) and apamin to displace bound 125I-charybdotoxin, a novel property for K+ channels. These unusual pharmacological characteristics suggest a unique structure for the red cell Gardos channel.

Poisonings requiring admission to the pediatric intensive care unit: A 5-year review

Abstract Background. Poisonings represent a significant number of preventable admissions to the pediatric intensive care unit (PICU), but data about poisonings requiring PICU-level care are limited. Objectives. To identify the demographics of patients admitted with poisonings and characterize their clinical courses related to their poisoning. Methods. All poisonings over a 5-year period (2008–2012) at an academic medical center in New England were retrospectively reviewed using electronic medical records in an observational case series. Poisonings were identified using key search terms within an admissions database. Results. There were 273 admissions for poisonings, which represent 8% of total PICU admissions over this time period. The poisonings were unintentional in 148 (54%) cases and intentional in 125 (46%). The vast majority of poisonings occurred in patients either 3 years or below (N = 121, 44%) or 13 years or above (N = 124, 45%). Most (96%) admissions were for less than 48 h and 41% were for less than 24 h. Mean PICU length of stay was 1.2 + 0.7 days. A total of 468 substances were ingested in 54 different drug classes, with analgesics and antidepressants being the most common. Eighty-five (31%) poisonings were polypharmaceutical. The most commonly used therapies were naloxone, activated charcoal, and benzodiazepines. Twenty-seven patients (10%) received mechanical ventilation. There was one fatality, an adolescent with a polypharmacy overdose in a suicide attempt. Conclusion. Pediatric poisonings are a significant percentage of admissions to the PICU. The majority of poisonings are non-fatal, require supportive care, close monitoring, and some specific treatment. Drug classes causing poisonings have changed to a higher percentage of opioids in younger patients and atypical antidepressants in adolescents.