Robert J. Boots

Fatal encephalitis due to novel paramyxovirus transmitted from horses

BACKGROUND In September, 1994, an outbreak of severe respiratory disease affected 18 horses, their trainer, and a stablehand in Queensland, Australia. Fourteen horses and one human being died. A novel virus was isolated from those affected and named equine morbillivirus (EMV). We report a case of encephalitis caused by this virus. FINDINGS A 35-year-old man from Queensland had a brief aseptic meningitic illness in August, 1994, shortly after caring for two horses that died from EMV infection and then assisting at their necropsies. He then suffered severe encephalitis 13 months later, characterised by uncontrolled focal and generalised epileptic activity. Rising titres of neutralising antibodies to EMV in the patients serum at the time of the second illness suggested an anamnestic response. Distinctive cortical changes were shown on magnetic resonance neuroimaging and histopathological examination of the brain at necropsy. Immunohistochemistry and electronmicroscopy of brain tissue revealed pathology characteristic of the earlier cases of EMV infection. PCR on cerebrospinal fluid taken during the second illness, brain tissue, and serum retained from the original illness resulted in an amplified product identical to that previously described from EMV. INTERPRETATION The results of serology, PCR, electronmicroscopy, and immunohistochemistry strongly suggest that EMV was the cause of this patients encephalitis, and that exposure to the virus occurred 3 months before the fatal illness.

Physical Therapy for the Critically Ill in the Icu: A Systematic Review and Meta-analysis*

Objective:The purpose of this systematic review was to review the evidence base for exercise in critically ill patients. Data Sources and Study Selection:Using keywords critical care and physical therapy and related synonyms, randomized controlled trials, meta-analyses, and systematic reviews were identified through electronic database searches and citation tracking. Clinical trials with outcomes of mortality, length of hospital and ICU stay, physical function and quality of life, muscle strength, and ventilator-free days were included. Data Extraction and Synthesis:Two reviewers abstracted data and assessed quality independently. Effect sizes and 95% confidence intervals were calculated. From 3,126 screened abstracts, 10 randomized controlled trials and five reviews were found. The mean Physiotherapy Evidence Database score was 5.4. Overall there was a significant positive effect favoring physical therapy for the critically ill to improve the quality of life (g = 0.40, 95% confidence interval 0.08, 0.71), physical function (g = 0.46, 95% confidence interval 0.13, 0.78), peripheral muscle strength (g = 0.27, 95% confidence interval 0.02, 0.52), and respiratory muscle strength (g = 0.51, 95% confidence interval 0.12, 0.89). Length of hospital (g = –0.34, 95% confidence interval –0.53, –0.15) and ICU stay (g = –0.34, 95% confidence interval –0.51, –0.18) significantly decreased and ventilator-free days increased (g = 0.38, 95% confidence interval 0.16, 0.59) following physical therapy in the ICU. There was no effect on mortality. Conclusion:Physical therapy in the ICU appears to confer significant benefit in improving quality of life, physical function, peripheral and respiratory muscle strength, increasing ventilator-free days, and decreasing hospital and ICU stay. However, further controlled trials of better quality and larger sample sizes are required to verify the strength of these tentative associations.

Augmented renal clearance: implications for antibacterial dosing in the critically ill.

The prescription of pharmaceuticals in the critically ill is complicated by a paucity of knowledge concerning the pharmacokinetic implications of the underlying disease state. Changes in organ function can be dramatic in this population, both as a consequence of the primary pathophysiology and in response to clinical interventions provided. Vascular tone, fluid status, cardiac output and major organ blood flow can be significantly altered from baseline, influencing the volume of distribution and clearance of many commonly prescribed agents.Although measurable endpoints can be used to titrate doses for many drugs in this setting (such as sedatives), for those agents with silent pharmacodynamic indices, enhanced excretory organ function can result in unexpectedly low plasma concentrations, leading to treatment failure. This is particularly relevant to the use of antibacterials in the critically ill, where inadequate, inappropriate and/or delayed prescription can have significant effects on morbidity and mortality.Augmented renal clearance (ARC) refers to enhanced renal elimination of circulating solute and is being described with increasing regularity in the critically ill. However, defining this process in terms of current measures of renal function is problematic, as although the glomerular filtration rate (GFR) is largely considered the best index of renal function, there is no consensus on an upper limit of normal. In addition, the most readily available and accurate estimate of the GFR at the bedside is still widely debated. From a pharmacokinetic point of view, ARC can result in elevated renal elimination and subtherapeutic plasma concentrations of pharmaceuticals, although whether this process solely involves augmented filtration (as opposed to enhanced tubular secretion and/or reabsorption) remains uncertain.The primary contributors to this process are likely to be the innate immune response to infection and inflammation (with its associated systemic and haemodynamic consequences), fluid loading and use of vasoactive medications. The resultant increase in cardiac output and renal blood flow prompts enhanced glomerular filtration and drug elimination. Current evidence suggests that young patients without preexisting co-morbidity or organ dysfunction who present with trauma are most likely to manifest ARC. As this phenomenon has received little attention in the literature, dose modification has rarely been considered.However, with increasing data supporting the concept, and many investigators demonstrating subtherapeutic concentrations of drugs in the critically ill, consideration of ARC and alternative dosing regimens is now mandatory, both to improve the likelihood of treatment success and to reduce the rate of development of antibacterial resistance.

Treatment of partial-thickness burns: A prospective, randomized trial using transcyte

Background:  The purpose of the present study was to compare the effectiveness of three burns dressings (TransCyte, a bio‐engineered skin substitute; Biobrane; and Silvazine cream (silver sulphadiazine and 0.2% chlorhexidine)), in treating children with partial‐thickness burns. The primary objective was to determine the days until ≥90% re‐epithelialization. The secondary objectives were to evaluate the number of wounds requiring autografting and the number of dressing changes/local wound care required.

Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*.

Objective:To describe the prevalence and natural history of augmented renal clearance in a cohort of recently admitted critically ill patients with normal plasma creatinine concentrations. Design:Multicenter, prospective, observational study. Setting:Four, tertiary-level, university-affiliated, ICUs in Australia, Singapore, Hong Kong, and Portugal. Patients:Study participants had to have an expected ICU length of stay more than 24 hours, no evidence of absolute renal impairment (admission plasma creatinine < 120 µmol/L), and no history of prior renal replacement therapy or chronic kidney disease. Convenience sampling was used at each participating site. Interventions:Eight-hour urinary creatinine clearances were collected daily, as the primary method of measuring renal function. Augmented renal clearance was defined by a creatinine clearance more than or equal to 130 mL/min/1.73 m2. Additional demographic, physiological, therapeutic, and outcome data were recorded prospectively. Measurements and Main Results:Nine hundred thirty-two patients were admitted to the participating ICUs over the study period, and 281 of which were recruited into the study, contributing 1,660 individual creatinine clearance measures. The mean age (95% CI) was 54.4 years (52.5–56.4 yr), Acute Physiology and Chronic Health Evaluation II score was 16 (15.2–16.7), and ICU mortality was 8.5%. Overall, 65.1% manifested augmented renal clearance on at least one occasion during the first seven study days; the majority (74%) of whom did so on more than or equal to 50% of their creatinine clearance measures. Using a mixed-effects model, the presence of augmented renal clearance on study day 1 strongly predicted (p = 0.019) sustained elevation of creatinine clearance in these patients over the first week in ICU. Conclusions:Augmented renal clearance appears to be a common finding in this patient group, with sustained elevation of creatinine clearance throughout the first week in ICU. Future studies should focus on the implications for accurate dosing of renally eliminated pharmaceuticals in patients with augmented renal clearance, in addition to the potential impact on individual clinical outcomes.

Pharmacokinetics of Colistin Methanesulfonate and Colistin in a Critically Ill Patient Receiving Continuous Venovenous Hemodiafiltration

Intravenous colistin methanesulfonate (CMS) is increasingly the last line of defense for multidrug-resistant gram-negative bacteria and is now being used as “salvage” therapy in critically ill patients ([1][1], [7][2], [9][3], [11][4]). CMS is converted in vivo to colistin, and these two

Toward Improved Surveillance: The Impact of Ventilator-Associated Complications on Length of Stay and Antibiotic Use in Patients in Intensive Care Units

BACKGROUND Hospitals and quality improvement agencies are vigorously focusing on reducing rates of hospital-acquired infection. Ventilator-associated pneumonia (VAP) is notoriously difficult to diagnose and surveillance is thwarted by the subjectivity of many components of the surveillance definition. Alternative surveillance strategies are needed. Ventilator-associated complications (VAC) is a simple, objective measure of respiratory deterioration. METHODS VAC is defined by increases in fraction of inspired oxygen (FiO(2)) by ≥ 15% or positive end-expiratory pressure (PEEP) by ≥ 2.5 cm H(2)O lasting ≥ 2 days after stable or decreasing FiO(2) or PEEP lasting ≥ 2 days. We retrospectively assessed patients on mechanical ventilation for ≥ 48 hours in our study intensive care unit (ICU) using electronic medical record data. We analyzed the association between VAC and clinical diagnoses, ICU length of stay, duration of mechanical ventilation, antibiotic use, and mortality. RESULTS We assessed 153 patients with VAC and 390 without VAC. VAC events were associated with significantly increased ICU length of stay, duration of mechanical ventilation, and consumption of broad-spectrum antibiotics but not with longer hospital stays or ICU mortality. CONCLUSIONS Surveillance for VAP is subjective and labor intensive. VAC is an objective measure which can be readily obtained from electronic records. It is associated with adverse outcomes and increased broad-spectrum antibiotic usage. VAC may be a useful surveillance tool. The utility of VAC prevention bundles merits assessment.

Reduced inspiratory muscle endurance following successful weaning from prolonged mechanical ventilation.

STUDY OBJECTIVES Respiratory muscle weakness and decreased endurance have been demonstrated following mechanical ventilation. However, its relationship to the duration of mechanical ventilation is not known. The aim of this study was to assess respiratory muscle endurance and its relationship to the duration of mechanical ventilation. DESIGN Prospective study. SETTING Tertiary teaching hospital ICU. PATIENTS Twenty subjects were recruited for the study who had received mechanical ventilation for > or = 48 h and had been discharged from the ICU. MEASUREMENTS FEV1, FVC, and maximal inspiratory pressure (P(I(max)) at functional residual capacity were recorded. The P(I(max)) attained following resisted inspiration at 30% of the initial P(I(max)) for 2 min was recorded, and the fatigue resistance index (FRI) [P(I(max)) final/P(I(max))initial] was calculated. The duration of ICU length of stay (ICULOS), duration of mechanical ventilation (MVD), duration of weaning (WD), and Charlson comorbidities score (CCS) were also recorded. Relationships between fatigue and other parameters were analyzed using the Spearman correlations (rho). RESULTS Subjects were admitted to the ICU for a mean duration of 7.7 days (SD, 3.7 days) and required mechanical ventilation for a mean duration of 4.6 days (SD, 2.5 days). The mean FRI was 0.88 (SD, 0.13), indicating a 12% fall in P(I(max)), and was negatively correlated with MVD (r = -0.65; p = 0.007). No correlations were found between the FRI and FEV1, FVC, ICULOS, WD, or CCS. CONCLUSIONS Patients who had received mechanical ventilation for > 48 h have reduced inspiratory muscle endurance that worsens with the duration of mechanical ventilation and is present following successful weaning. These data suggest that patients needing prolonged mechanical ventilation are at risk of respiratory muscle fatigue and may benefit from respiratory muscle training.

Cefepime versus cefpirome: the importance of creatinine clearance.

Standard dosage recommendations for &bgr;-lactam antibiotics can result in very low drug levels in intensive care (IC) patients without renal dysfunction. We compared the pharmacokinetics of two fourth-generation cephalosporins, cefepime and cefpirome, and examined the relationship of drug clearance (CL) to creatinine clearance (CLCR). Two separate but similar pharmacokinetic studies (which used 2 g twice daily for each antibiotic) were conducted. Blood was sampled after an initial and a subsequent antibiotic dose. Drug plasma concentrations were measured, and pharmacokinetic analyses were conducted and compared. The pharmacokinetics of cefepime and cefpirome are similar in IC patients. Any differences in drug CL can largely be attributed to differences in CLCR. Despite normal plasma creatinine concentrations, 54% of patients’ antibiotic concentrations were less than the minimum inhibitory concentration (MIC) (4 mg/L) for >20% of the dosing interval. Thirty-four percent of patients had CLCR >144 mL/min (20% higher than the expected maximum of 120 mL/min). Only CLCR was an independent predictor of antibiotic CL. Time above MIC was predicted only by CLCR. Some IC patients have a very large CLCR, which results in very low levels of studied antibiotics. Either shortening the dosage interval or using continuous infusions would prevent low levels and keep troughs above the MIC for longer periods. In view of the lack of bedside measurement of cephalosporin levels, we suggest that more frequent use be made of CLCR to allow prediction of small concentrations clinically.

Clinical utility of hygroscopic heat and moisture exchangers in intensive care patients.

OBJECTIVE To compare the degree of bacterial circuit colonization, frequency of ventilator-associated pneumonia (VAP), character of respiratory secretions, rewarming of hypothermic patients, disposable costs, and air flow resistance in intensive care patients ventilated using either a heat and moisture exchanger (HME) or hot water (HW) humidifier circuit. DESIGN A prospective, randomized blinded trial of patients in the intensive care unit undergoing mechanical ventilation. SETTING A metropolitan teaching hospital. PATIENTS One hundred sixteen patients undergoing mechanical ventilation for a minimum period of 48 hrs were enrolled. INTERVENTIONS Patients were randomized to three ventilation groups using a) an HW circuit with a 2-day circuit change (n = 41); or b) a bacterial-viral filtering HME in the circuit, with either a 2-day (n = 42); or c) a 4-day circuit change (n = 33). MEASUREMENTS AND MAIN RESULTS Circuit colonization was assessed using quantitative culture of washings taken from the circuit tubing and semiquantitative culture of swabs from the Y connectors. Sixty-seven percent of HW circuits became contaminated compared with 12% in the two HME groups (p < .0001). Median colony counts were lower in the HME groups (p < .0001). If circuits at first circuit change were contaminated in the HW group, 89% of subsequent circuit changes became contaminated compared with 0% and 25% for the 2- and 4-day HME groups, respectively. The frequency of VAP, the time to resolution of admission hypothermia, and the volume and fluidity of secretions were similar for all groups. The resistance of the HME after 24 hrs of use was < 0.025 cm H2O/L at gas flows of 40 L/min. HME use resulted in a cost reduction of