Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. ...Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg 4 to 6 L in an 80-kg adult during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg ≤2 to 3 L), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.
Background In dogs undergoing vertebral column stabilization, post-operative computed tomography (CT) evaluates implant placement. The impact on the interpretation of metallic artifact associated ...with titanium implants in dogs remains to be established. Our objective was to quantify metallic artifact on CT associated with titanium pedicle screws. Methods The study design included an in vitro model and a retrospective review of 11 dogs with vertebral column stabilization. Twenty four titanium pedicle screws (6 each: 2.0 mm, 2.7 mm, 3.5 mm, and 4.5 mm) were inserted into a 20% ballistic gel, and CT scan of the construct was performed. Three blinded raters used a bone window to measure the maximum width (effective size) of each screw, one rater measured effective size using an ultrawide window and 45 titanium pedicle screws (3×2.0 mm, 5×2.7 mm, 30×3.5 mm, and 7×4.5 mm) in 11 clinical cases. Effective size measurements were compared to actual screw sizes. Results The effective size was 26.9–43.8%, 9.2–18.5%, and 21.1–30.5% larger than the actual size for the in vitro system (bone window), in vitro system (ultrawide window), and clinical cases, respectively. The mean gross difference for the in vitro measurements varied by implant size ( p < 0.001) and was positively correlated with implant size ( r = 0.846), but the mean percentage difference was negatively correlated with implant size ( p < 0.001). Overestimation was larger for the in vitro model bone window compared to the ultrawide window ( p < 0.001) and clinical cases ( p = 0.001). Conclusion Metallic artifact associated with titanium pedicle screws on CT resulted in an overestimation of screw size. This information might aid in the interpretation of implant placement on post-operative imaging.
Background
Progressive myelomalacia (PMM) is a catastrophic disease associated with acute intervertebral disc extrusion (IVDE). Published data on the clinical characteristics of this disease are ...limited.
Objective
To describe the onset and progression of clinical signs of PMM in a large case cohort.
Animals
Fifty‐one dogs, 18 with histopathologically confirmed PMM, 33 presumptively diagnosed based on clinical signs and diagnostic imaging.
Methods
Retrospective study. Dogs with confirmed IVDE and either a histopathologic diagnosis of PMM or a high clinical suspicion were identified by medical record search. Data on nature and progression of signs were extracted.
Results
Twenty‐four of 51 dogs were Dachshunds. T12–T13 was the most common site of disc extrusion (12 of 56), and 18 of 55 of mid‐to‐caudal lumbar discs (between L3 and L6) were affected. Onset of PMM signs ranged from present at first evaluation (17/51) to 5 days after presentation, with 25 of 51 cases developing signs within 48 hours. Progression of signs from onset of PMM to euthanasia or death, excluding 7 cases euthanized at presentation, ranged from 1 to 13 days with 23 being euthanized within 3 days. Nonspecific systemic signs were documented in 30 of 51 dogs.
Conclusion and Clinical Importance
The majority of dogs developed PMM within 2 days of presentation and was euthanized within another 3 days. However, onset can be delayed up to 5 days after presentation with progression to euthanasia taking as long as 2 weeks. Mid‐to‐caudal lumbar discs might be associated with an increased risk of PMM.
Objective: Our objective was to determine whether long-term treatment of young patients with cystic fibrosis (CF) with dornase alfa maintains lung function and reduces respiratory tract ...exacerbations.
Study design: This was a 96-week, randomized, double-blind, placebo-controlled trial involving 49 CF centers. Inclusion criteria were age 6 to 10 years and forced vital capacity ≥ 85% predicted. Patients were excluded for hospitalization for complications of CF within 2 months and use of dornase alfa within 6 months. Patients were treated with dornase alfa 2.5 mg or placebo once daily with a jet nebulizer and a compressor.
Results: Patients were randomized, 239 to dornase alfa and 235 to placebo. At baseline the mean age was 8.4 years, the mean forced expiratory volume in 1 second 95% predicted, the mean forced expiratory flow, midexpiratory phase 85% predicted, and the mean forced vital capacity 102% predicted. At 96 weeks the treatment benefit for dornase alfa compared with placebo in percent predicted (mean ± SE) was 3.2 ± 1.2 for forced expiratory volume in 1 second (
P = .006), 7.9 ± 2.3 for forced expiratory flow between 25% and 75% of vital capacity (
P = .0008), and 0.7 ± 1.0 for forced vital capacity (
P = .51). The risk of respiratory tract exacerbation was reduced by 34% in patients who received dornase alfa (relative risk 0.66,
P = .048). There was no statistically significant difference between the groups in changes in weight-for-age percentile. Adverse event profiles for the treatment groups were similar.
Conclusions: Treatment of young patients with CF with dornase alfa maintains lung function and reduces the risk of exacerbations over a 96-week period. (J Pediatr 2001;139:813–20)
BACKGROUND: Acute intervertebral disk herniation (IVDH) is a common cause of spinal cord injury in dogs and currently there is no proven medical treatment to counter secondary injury effects. Use of ...methylprednisolone sodium succinate (MPSS) or polyethylene glycol (PEG) as neuroprotectants is advocated but controversial because neither treatment has been tested in placebo‐controlled, randomized, blinded trials in dogs. HYPOTHESIS: Polyethylene glycol will improve the outcome of severe spinal cord injury caused by IVDH compared to MPSS or placebo. ANIMALS: Client‐owned dogs with acute onset of thoracolumbar IVDH causing paralysis and loss of nociception for <24 hours. METHODS: Dogs were randomized to receive MPSS, PEG, or placebo; drugs appeared identical and group allocation was masked. Drug administration was initiated once the diagnosis of IVDH was confirmed and all dogs underwent hemilaminectomy. Neurologic function was assessed 2, 4, 8, and 12 weeks postoperatively using an open field gait score (OFS) as the primary outcome measure. Outcomes were compared by the Wilcoxon rank sum test. RESULTS: Sixty‐three dogs were recruited and 47.6% recovered ambulation. 17.5% developed progressive myelomalacia but there was no association with group. There was no difference in OFS among groups. Although full study power was not reached, conditional power analyses indicated the futility of continued case recruitment. CONCLUSIONS: This clinical trial did not show a benefit of either MPSS or PEG in the treatment of acute, severe thoracolumbar IVDH when used as adjunctive medical treatment administered to dogs presenting within 24 hours of onset of paralysis.
Objectives
Acute intervertebral disc herniation is commonly managed by veterinary neurologists and surgeons. Anecdote suggests that patterns of management vary considerably and there is controversy ...surrounding many aspects of treatment. The goal of this study was to document patterns in management of acute spinal cord injury caused by acute intervertebral disc herniation among these two groups to aid in future discussions on best practices.
Methods
A survey querying diagnostic, medical and surgical practices for dogs with acute intervertebral disc herniation was distributed to diplomates on the databases of the American College of Veterinary Surgeons and the American College of Veterinary Internal Medicine (Neurology).
Results
Responses were received from 314 board‐certified veterinary surgeons and neurologists. Both groups handled timing of decompression, surgical approach, and most postoperative recommendations in a similar fashion. Case volume differed between groups, with 77% of neurologists and 18% of surgeons managing ≥50 cases of acute intervertebral disc herniation per year. MRI was used most frequently as a diagnostic tool by neurologists (75%), while CT was used most commonly by surgeons (58%). Corticosteroids were routinely administered as a neuroprotective strategy by 34% of surgeons and 11% of neurologists. Disc fenestration was performed “always” or “most of the time” by 69% of neurologists and 36% of surgeons.
Clinical Importance
Understanding the common practices in the management of canine acute intervertebral disc herniation can provide a springboard for future discussions regarding the best practices in diagnosing and treating this disease.
N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have ...been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters.
Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model.
The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model.
A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.
Summary
Background
Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics.
Objective
We sought to identify in ...adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease‐related factors influence these associations.
Methods
We performed a genome‐wide association study of FeNO through meta‐analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium.
Results
We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome‐wide significant level (P = 1.6 × 10−7) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10−7) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values.
Conclusions and Clinical Relevance
This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.
Background
There is little evidence‐based information available to guide treatment of refractory epilepsy in dogs. The antiepileptic drug levetiracetam (LEV) is administered to dogs, although its ...safety and efficacy are unknown.
Objective
To evaluate the safety and efficacy of LEV as adjunctive therapy for refractory epilepsy in dogs.
Animals
Thirty‐four client‐owned dogs with idiopathic epilepsy.
Methods
Randomized, blinded trial involving dogs resistant to phenobarbital and bromide. Dogs received LEV (20 mg/kg PO q8h) or placebo for 16 weeks, and after a 4‐week washout were crossed over to the alternate treatment for 16 weeks. Owners kept records on seizure frequency and adverse events. Hemogram, chemistry profile, urinalysis, and serum antiepileptic drug concentrations were evaluated at established intervals.
Results
Twenty‐two (65%) dogs completed the study. Weekly seizure frequency during the 1st treatment period decreased significantly during LEV administration relative to baseline (1.9 ± 1.9 to 1.1 ± 1.3, P = .015). The reduction in seizures with LEV was not significant when compared to placebo (1.1 ± 1.3 versus 1.5 ± 1.7, P = .310). The most common adverse event was ataxia, with no difference in incidence between LEV and placebo (45 versus 18%, P = .090). No changes in laboratory parameters were identified and owners reported an improved quality of life (QOL) with LEV compared to placebo (QOL score 32.7 ± 4.3 versus 29.4 ± 4.5, P = .028).
Conclusions and Clinical Importance
Adjunctive treatment with LEV appears safe in epileptic dogs. Efficacy of LEV over placebo was not demonstrated, although the power of the study was limited. Further evaluation of LEV as treatment for epilepsy in dogs is warranted.
Electroencephalographic (EEG) data were collected from a sample of institutionalized infants and young children in Bucharest, Romania, and were compared with EEG data from age-matched children from ...the local community who had never been institutionalized and who were living with their families in the Bucharest area. Compared with the never-institutionalized group, the institutionalized group showed a pattern of increased low-frequency (theta) power in posterior scalp regions and decreased high-frequency (alpha and beta) power, particularly at frontal and temporal electrode sites. This finding is consistent with EEG studies of children facing environmental adversity and children with learning disorders. The institutionalized group also showed less marked hemispheric EEG asymmetries than the never-institutionalized group, particularly in the temporal region. The results are discussed in the context of two models: that the pattern of EEG in the institutionalized children reflects a maturational lag in nervous system development, or that it reflects tonic cortical hypoactivation.
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