Received Repeat Doses Research Articles

Review: multiple doses of antenatal corticosteroids prevent preterm neonatal respiratory disease more than a single dose

ED FROM Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 2007;(3):CD003935. Correspondence to:...

Outcomes at 2 Years of Age After Repeat Doses of Antenatal Corticosteroids

A recent meta-analysis of randomized trials suggests a lowered risk of neonatal respiratory distress syndrome among children whose mothers received repeat doses of corticosteroids antenatally compared to those whose mothers received a single course, but the longer-term effects-if any-remain uncertain. This study enrolled women at risk of preterm delivery who had received an initial course of steroid therapy a week or more previously. Participants were randomly assigned to receive either an intramuscular injection of 11.4 mg of betamethasone or a saline placebo, weekly until 32 weeks' gestation. Of 1047 children who were assessed at age 2 years, 521 had been exposed to repeated steroid treatment while 526 had been exposed to only one course of steroids and then placebo. Evaluative instruments included the Psychomotor Developmental Index and the Mental Developmental Index of the Bayley Scales of Infant Development as well as the Child Behavior Checklist.. The rates of survival without major disability were similar in the repeat-steroid and placebo groups (84% and 81%, respectively), and there were no significant differences in weight, height, head circumference, body size, blood pressure, respiratory morbidity, the incidence of asthma, the incidence or severity of neurosensory impairment, the combination of neurosensory impairment and death, or the use of health services. When the results were analyzed according to the number of repeat steroid doses received, no significant interaction between the effect of treatment and either survival free of major disability or body size was seen. There were no differences in the incidence of problem behaviors itemized in the child behavior checklist, with the exception of attention problems, which were more common among children exposed to repeat doses of steroids (6.0% vs. 3.2%, P = 0.04; RR = 1.87 [1.03-3.42]). The mortality rates were 5% to 6% in both groups. The investigators concluded that repeat steroid doses were associated with reduced neonatal morbidity without an increase in neurosensory impairment or reduced body size.

Characterizing Factor VIII Inhibitor Resistance of Platelet-Delivered Factor VIII in the Treatment of Hemophilia A.

Gene therapy strategies directed at expressing Factor (F) VIII in megakaryocytes may have several potential advantages in the treatment of severe hemophilia A. Among these is that platelet (p) FVIII may be protected from circulating inhibitors. We have previously described a murine transgenic line that expressed human B-domainless FVIII in a megakaryocyte-specific fashion and that this pFVIII was localized to within alpha granules. We also showed that these platelets contained FVIII equivalent to an infusion of 9% human FVIII into FVIIInull mice. We further showed that these pFVIII mice, on a FVIIInull murine background, formed stable clots in a FeCl3 carotid artery injury model. We then tested the ability of infused anti-human FVIII inhibitors in this setting. Using up to 100 μL of ESH8 monoclonal antibody (Ab) to the FVIII C2 light chain (1 μg/mL), anti-human polyclonal Ab (11 mg/mL) or a monoclonal Ab to the A2 domain (5 mg/mL), we were unable to alter thrombus formation in the carotid artery model. However, by using a 1:1:1 mixture of these inhibitors, we were able to show a dose-response curve. None of these mice developed thrombocytopenia suggesting that pFVIII is not exposed on the surface of circulating platelets. We then compared these studies to an acute infusion of the same inhibitor mixture in a FVIIInull mice receiving a 25% hFVIII correction. These studies showed that pFVIII/FVIIInull mice were ∼100-fold more resistant to inhibitors than plasma FVIII infusion into a FVIIInull mice in the carotid artery injury model. Since we had shown in the pFVIII mice that the FVIII is stored in alpha-granules, which can also store circulating Ab, we wondered whether the pFVIII/FVIIInull mice would be more sensitive to inhibitors when exposed in a chronic model where animals receive repeat doses of the inhibitor mixture. We therefore infused 3 doses of the inhibitor over 10 days, measured plasma and platelet inhibitor levels, and found that despite detectable stores of inhibitor within their platelets, these mice still demonstrated a comparable ability to form thrombosis as mice in the acute model with comparable plasma inhibitor levels. These studies suggest that pFVIII provides limited improved protection in mice with inhibitors comparable to <6 Bethesda Units (BU) in both acute and chronic models of inhibitor. Also, the presence of inhibitors within alpha-granules does not significantly inhibit the ability of these mice to form a clot. Our findings differ from a recent report of the efficacy of pFVIII in a tail vein survival model where pFVIII effectively protected mice from exsanguinations even in the presence of >100 BU/mL. We propose that the difference in outcome is due to the tail model being extremely sensitive to even low levels of pFVIII as exsanguinated, hypovolemic mice likely shunt blood away from their tail veins, and platelet activation and granular release are occurring in a low flow setting, while the FeCl3 model used in this report requires a plasma equivalency of >3–5% human FVIII to show even partial correction.

Analyzing Prophylactic Antibiotic Administration in Procedures Lasting More than Pour Hours: Are Published Guidelines Being Followed?

Published guidelines for surgical antibiotic prophylaxis recommend that an appropriately selected and administered antibiotic should be repeated in a timely manner in lengthy procedures. To assess concordance with published guidelines we reviewed the prophylactic antibiotic usage in procedures lasting more than 4 hours at a 500-bed university hospital. The records of 300 procedures longer than 4 hours in duration from the gastrointestinal, neurosurgery, and vascular surgery services were retrospectively reviewed. Analysis was confined to the usage of antibiotics in a prophylactic setting. Using a liberal interpretation of the American College of Surgeons, Centers for Disease Control and Prevention, Surgical Infection Society, and Medical Letter Guidelines each case was evaluated for the appropriateness of the antibiotic selection, the interval between the first dose and the skin incision, and the timeliness of repeat dosing. Twenty-five patients (8.3%) did not receive any antibiotic coverage at all. One hundred ninety cases (63.3%) received the correct antibiotic, but only 96 (32%) received it in a timely manner before surgery. Nine patients (3%) in 300 cases received repeat doses at the correct time for the entire duration of the surgery in complete compliance with the published guidelines. We conclude that antibiotic prophylaxis of lengthy procedures is rarely in accordance with published guidelines.

Do We Use Too Much Antenatal Betamethasone?

To review and rationalize the liberal use of antenatal betamethasone in the setting of threatened preterm birth. A retrospective review was performed using the charts of all patients at Ste-Justine Hospital, Montreal QC, who received antenatal betamethasone between 01 April 1997 and 31 March 1998. Initial treatment consisted of 2 doses of 12 mg IM given 24 hours apart. Repeat doses of 12 mg weekly were administered at the discretion of the treating physician. Optimal antenatal betamethasone therapy was defined as delivery within 1 week of initial treatment, prior to 34 weeks. Aside from number and timing of doses, other factors analyzed included: gestational age at admission and delivery, diagnosis associated with threatened preterm birth (PTB), number of hospital admissions, and delay between re-admission and delivery. Of the 334 patients identified, 82 (25%) received optimal treatment. Of the remaining 252 patients, 204 (81%) received repeat doses. In the repeat dose group, 112 (55%) women delivered after 34 weeks, while 70 of the 92 remaining patients were hospitalized until delivery. The other 22 patients who received serial doses were discharged at least once prior to delivery; of these patients, 8 were re-admitted more than 24 hours pre-delivery (i.e., adequate time for re-treatment), while 14 were not, but only 6 of these were delivered urgently. Thus, a maximum of 60 patients (25% of repeat doses) could potentially have benefited from this approach. Of the 48 patients not receiving repeat doses, 37 (77%) delivered after 34 weeks. Five remained hospitalized, and 6 were discharged prior to delivery and re-admitted (2 patients > 24 hr and 4 patients < 24 hr from delivery). This represented a potential underutilization of betamethasone by 3% (11/334) of the patients, but only 1.8% (6/334) were of less than 32 weeks' gestation. This study demonstrated the difficulty in predicting which of the patients presenting with threatened preterm birth would actually go on to deliver during the window of benefit of antenatal betamethasone therapy. Our desire to permit all premature fetuses to profit from the positive effects of this therapy must be balanced by a reserve in exposing too many to too much. Use of antenatal betamethasone in our unit has significantly decreased since this review.

Amifostine for protection from antineoplastic drug toxicity.

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.

Gastrointestinal Decontamination for Acute Poisoning

Gastric decontamination remains an important element in the therapy of pediatric poisoning; however, several issues remain unresolved. Additional studies, particularly in the clinical setting, are necessary to establish optimal therapeutic recommendations. Based on the data presented in this review, the following general recommendations can be made for gastric decontamination in children: If it is necessary to remove an ingested toxin, ipecac syrup is the preferred method if contraindications to its use are not present. The dose should be 30 ml in children older than 1 year of age and 10 ml in children 6 to 12 months of age. Pending further studies, the use of emetics in children younger than 6 months of age cannot be generally recommended, particularly in the home setting. Gastric lavage should be considered to be of very limited use in pediatric patients. Lavage using small nasogastric tubes, except under special circumstances, is nonproductive and cannot be advocated. If it must be used, a large-bore orogastric hose should be used. Administration of activated charcoal prior to lavage should be considered. In situations in which prompt induction of emesis is not possible or contraindications to emesis exist, activated charcoal followed by, or mixed with, a cathartic (preferably sorbitol) should be used as an alternative to removal of gastric contents. Patients with significant symptoms from ingestion requiring hospitalization should receive repeat doses of charcoal and cathartic until symptoms resolve. Activated charcoal should be given in conjunction with other appropriate therapies. Although the data to substantiate this recommendation are limited, particularly in pediatric patients, it is a benign therapy that holds promise of increasing drug elimination.