A current concept of trauma-induced multiorgan failure.

Trauma deaths continue to show a trimodal distribution: immediately at the scene, within the first 24 hours during initial resuscitation, and in the next 3 to 4 weeks as a result of multiple organ failure.(1) Failure to resuscitate adequately in the emergency department can lead to acidosis, hypothermia, and coagulopathy, which can result in multiple organ failure and cause death in these patients. Our current understanding of the initial response to shock and trauma and the development of the systemic inflammatory response syndrome and progressive organ failure is one of a continuum initiated and perpetuated by inflammation and inflammatory mediators. The pathophysiologic character, diagnosis, prevention, and treatment of traumatic injury-induced multiple organ failure are discussed.

Emergency department presentation of pituitary apoplexy.

Pituitary apoplexy is an acute infarction of pituitary gland, and potentially life-threatening condition that may be highly variable in its clinical presentation. We report a 54-year-old man presenting to the emergency department with an isolated oculomotor nerve palsy. Computed tomography (CT) scan revealed an isodense mass within sellar region and subsequently, magnetic resonance imaging (MRI) revealed a pituitary apoplexy causing a compression of right oculomotor nerve. The patient received hydrocortisone immediately, and did well with medical management. An isolated oculomotor nerve palsy is very rarely the presenting sign of pituitary apoplexy. When correctly diagnosed and treated, the third nerve palsy appears to be reversible. A pathophysiology, differential diagnosis, and treatment is described.

Occupational exposures to blood among emergency medicine residents.

OBJECTIVES: To investigate the epidemiologic characteristics of potentially infectious occupational exposures to blood among emergency medicine (EM) residents. METHODS: A SAEM-sponsored multiple-choice survey was administered anonymously to all EM residents participating in the 1998 American Board of Emergency Medicine in-service examination. Survey questions included resident demographics, use of universal precautions, frequency and types of exposures to blood, and exposure reporting. Residents who experienced at least one exposure were then asked to complete an additional set of questions referring only to their latest exposure. Mean values were calculated for each variable and differences between groups were compared by chi-square analysis. RESULTS: Three thousand one hundred sixty-two surveys were distributed to the resident participants, and 2,985 surveys (94.4%) were returned. Of the participants, 56.1% reported at least one exposure to blood during their EM training. The frequency of this self-reported exposure increased with advancing EM level of training (43% EM-1, 58% EM-2, 64% EM-3, 76% EM-4, p<0.001). Of these residents, 36.6% always followed universal precautions, 54% frequently, and 9.4% sometimes, rarely, or never. Those individuals who "always" followed universal precautions reported significantly fewer exposures than those who did not (p<0.005). The latest exposures were most commonly caused by a solid needle or sharp object (39.4%), by a hollow-bore needle (30.6%), or by eye splashes (17.2%). Of these exposures, 71.7% occurred in the ED setting, and only 46.7% of these exposures were reported to health care providers. CONCLUSION: Emergency medicine residents are frequently exposed to blood, most commonly due to puncture injuries by sharp objects. The rate of exposure reporting is low, which may compromise appropriate postexposure counseling and prophylaxis.

Tuberculosis exposure risk in emergency medicine residents.

OBJECTIVES: To assess purified protein derivative (PPD) test surveillance and respiratory protection practices of emergency medicine (EM) residents, along with the prevalence of PPD test conversion and the development of active tuberculosis (TB) in EM residents. METHODS: The study instrument was an anonymous, self-reporting, multiple-choice survey administered to U.S. and Canadian EM residents. It was distributed for voluntary completion in conjunction with the American Board of Emergency Medicine's annual in-service examination, which was administered February 25, 1998. RESULTS: A total of 89.3% (n = 2,985) of residents eligible to complete the survey completed at least part of it. The majority of residents are PPD-tested once a year. The prevalence of PPD test conversions in EM residents was between 1.4% (36/2,575) and 2.0% (52/2,575). Of the residents who PPD test-converted, the ED was most often the perceived area of TB source exposure (n = 15). Two residents (0.08%) reported having developed active TB, including chest radiographic findings or clinical infection, which equals a 0.14% (95% CI = 0.005 to 0.31) risk of developing active TB over a three-year residency. Half of all the residents do not routinely wear National Institute for Occupational Safety and Health (NIOSH)-approved particulate filtration respirator (PFR) masks in patient encounters at risk for TB exposure. While more than a third of EM residents have not undergone fit testing for a NIOSH-approved PFR mask, the lack of routine easy availability of such masks is the most common reason they are not routinely worn by EM residents during at-risk encounters for TB transmission. CONCLUSIONS: Most surveillance PPD testing of EM residents is performed at intervals recommended by the CDC. TB control programs at institutions sponsoring EM residencies need to improve both compliance with PFR mask fit testing by EM residents and availability of approved PFR masks in appropriate areas of the ED. Despite poor compliance with personal respiratory protection in ED patient encounters at risk for TB transmission, the risk of an EM resident's developing active TB over a three-year residency is low.

Declining rate of cricothyrotomy in trauma patients with an emergency medicine residency: implications for skills training.

OBJECTIVE: To report the change in cricothyrotomy rate with emergency medicine (EM) residency development and to address the implications for training in this skill. METHODS: A retrospective chart review was used to determine the cricothyrotomy rate at a 1,000-bed urban Level-1 trauma center with EM, surgery, and anesthesiology residencies. All adult trauma patient visits to the ED between July 1, 1985, and June 30, 1995, were reviewed. The cricothyrotomy rate was defined as the total number of cricothyrotomies per trauma admissions during a study phase. RESULTS: The study period was divided into 3 phases. Phase 1 (academic years 1985-1989): prior to the inception of the EM residency; phase 2 (academic years 1990-1992): initiation and establishment of the residency; and phase 3 (academic years 1993-1994): full implementation of the EM residency. The cricothyrotoiny rate during phase 1 was 1.8% (95% CI: 1.6 to 2.0), vs 1.1% (95% CI: 0.0 to 2.8) and 0.2% (95% CI: 0.0 to 0.2) during phases 2 and 3, respectively. CONCLUSIONS: The cricothyrotomy rate decreased with the full implementation of the EM residency. Whether this trend was an effect of the presence of an EM faculty and residency training program, a parallel approach to airway management nationwide, or another unidentified factor will require further investigation. Nonetheless, given the increasing rarity of this procedure, it is likely that many EM, surgical, and anesthesiology residents will not acquire clinical experience with this technique during training.

Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:polyC12U in the treatment of HIV infection.

In this multicenter, randomized, double-blind study the activity of polyI:polyC12U administered with zidovudine was evaluated in the treatment of HIV infection. Thirty-six HIV-positive, pre-AIDS individuals (100-500 CD4+ cells/mm3) who had had at least six months of zidovudine therapy received polyI:polyC12U (400 or 700 mg) or placebo twice weekly with zidovudine. PolyI:polyC12U subjects with baseline CD4+ counts > or = 300/mm3 showed a trend towards reduced CD4+ loss versus placebo recipients. PolyI:polyC12U subjects were more likely to exhibit positive delayed-type hypersensitivity responses than placebo recipients. Placebo subjects crossing over to polyI:polyC12U therapy demonstrated improved CD4+ and delayed-type hypersensitivity responses. PolyI:polyC12U subjects with baseline CD4+ counts > or = 300/mm3 were less likely to develop AIDS than similar placebo subjects. PolyI:polyC12U therapy of HIV-positive subjects restored or stabilized immune function as indexed by delayed-type hypersensitivity reactivity and, in individuals with CD4+ counts > 300/mm3, abrogated CD4+ loss and reduced disease progression. PolyI:polyC12U was generally well-tolerated in this zidovudine-treated population. No subject discontinued therapy due to an adverse reaction or aberrant laboratory parameter.

Rapid improvement of acute pulmonary edema with sublingual captopril.

OBJECTIVE: To test the hypothesis that sublingual captopril produces a more rapid improvement of acute pulmonary edema (APE) than does placebo, when added to a standard regimen of O2, nitrates, morphine, and furosemide. METHODS: Prospective, randomized, double-blind, placebo-controlled clinical trial in an urban teaching hospital ED. Adults brought to the ED with APE were given captopril or placebo sublingually. Every 5 minutes a clinical APE distress score (APEX) was obtained. RESULTS: Over the first 40 minutes of treatment, the mean APEXs were significantly better for the patients given captopril [p < 0.001, F = 14.5, one-way (repeated-measures) analysis of variance (ANOVA)]. At 30 minutes, the patients given captopril had a mean APEX improvement of 43% (i.e., to 57% of initial distress); the group given the current standard regimen plus placebo improved only 25% (i.e., to 75% of initial distress; p = 0.03, multiway ANOVA). In addition, there was less respiratory failure necessitating mechanical ventilation in the captopril patients (9%) vs the placebo patients (20%), which did not achieve significance (p = 0.10, Fisher's exact test). CONCLUSION: In APE, the addition of sublingual captopril to the standard regimen of O2, nitrates, morphine, and furosemide produces more rapid clinical improvement than does the standard regimen alone.

Synergistic inhibition of AZT-resistant HIV by AZT combined with poly(I):poly(C12U), without synergistic toxicity to bone marrow progenitor cell elements.

Mutation of human immunodeficiency virus (HIV) to drug resistance is an obstacle to HIV containment, and may account for the transitory nature of the improvement in CD4 cell counts of patients receiving azidothymidine (AZT). The emergence of AZT-resistant (AZTR) virus might be suppressed if a second therapeutic could be added; however, such a regimen would have to confer not only additional control over HIV replication but also no additional toxicity, especially to bone marrow progenitor cells. In the present study, HIV was isolated from patients receiving AZT alone and was studied for sensitivity to the mismatched double-stranded RNA, poly(I):poly(C12U) (ampligen). In addition, the combination of poly(I):poly(C12U) plus AZT was studied in vitro for toxicity to bone marrow CFU-GM and in patients receiving combined therapy for bone marrow toxicity. HIV isolated from patients receiving AZT alone showed higher resistance to AZT than wildtype virus, but remained sensitive to poly(I):poly(C12U). Poly(I):poly(C12U) and AZT were synergistic in inhibiting all isolates of HIV tested, regardless of their AZTR phenotype. Furthermore, the combination of poly(I):poly(C12U) and AZT showed no toxicity in vitro to bone marrow CFU-GM compared to AZT alone. In 11 HIV infected individuals receiving the combinational regimen, bone marrow function gradually improved. These results indicate that poly(I):poly(C12U) was active against AZTR HIV, synergistic with AZT and did not convey added toxicity.

A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation, and impairment of cognition. In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined. Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale, and exercise treadmill performance. After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05).

Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome.

Levels of 2',5'-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls. Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft.

The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.

An hypothesis concerning optimal therapy in HIV disease.

Ampligen, a mismatched double stranded RNA, is hypothesized to be an ideal base therapy for HIV disease to which other agents, such as the nucleoside analogue, AZT, can be advantageously added. The unique properties of Ampligen which support this hypothesis include activation of immune cells, inhibition of virus replication by inducing an antiviral cellular state and inhibition of growth of neoplastic cells. Ampligen is synergistic with other agents being used or being tested for use in HIV disease and is without toxicity.

Mismatched double-stranded RNA, Ampligen (poly(I): poly(C12U), demonstrates antiviral and immunostimulatory activities in HIV disease.

Mismatched double-stranded RNA (Ampligen) has broad spectrum antiviral and immunomodulatory activities. These activities generate stabilization or improvement in three important surrogate markers of HIV disease progression. Patients with HIV disease treated with Ampligen do not become positive for p24 antigen, in contrast to patients treated with AZT or placebo. Viral burden can also be decreased in patients receiving Ampligen/AZT therapy. In vitro studies indicate that both AZT sensitive and AZT resistant viruses can be inhibited by Ampligen alone and are synergistically inhibited by Ampligen in combination with AZT. The immunomodulatory effects of Ampligen are manifested as a stabilization of CD4 counts. When Ampligen is combined with AZT, an increase in CD4 count is seen. Furthermore, a return or increase in delayed type hypersensitivity to mumps, Candida, and trichophyton was seen in approximately 70% of patients treated with Ampligen. The activity of Ampligen in HIV disease is due to its multifunctional activity as an antiviral and immune stimulating agent. The antiviral effect directly inhibits HIV-infection and other viruses which have been implicated in HIV disease acceleration and progression. The immunomodulatory activity can stabilize, increase, or restore immune function. This enhanced immune function can also lead to the further inhibition of additional infections associated with disease progression. Thus, Ampligen has multiple mechanisms of action against HIV disease.

The tertiary structure of the four-way DNA junction affords protection against DNase I cleavage.

The accessibility of phosphodiester bonds in the DNA of four-way helical junctions has been probed with the nuclease DNase I. Regions of protection were observed on all four strands of the junctions, that tended to be longer on the strands that are exchanged between the coaxially stacked pairs of helices. The protected regions on the continuous strands of the stacked helices were not located exactly at the junction, but were displaced towards the 3' side of the strand. This is the region of backbone that becomes located in the major groove of the opposed helix in the non-crossed, right-handed structure for the junction, and might therefore be predicted to be protected against cleavage by an enzyme. However, the major grooves of the structure remain accessible to the much smaller probe dimethyl sulphate.

Differential effects of human natural interferon-alpha and mismatched double-stranded RNA against a human renal cell carcinoma xenograft.

The antitumor effects of natural human IFN-alpha and mismatched dsRNA against the human renal cell carcinoma cell line 786-0 were studied both in a clonogenic soft agar assay and in the nude mouse. The 786-0 cells were sensitive in vitro to the antiproliferative effects of IFN-alpha in a dose-response manner, up to 3000 IRU/ml. These cells were also sensitive, in a dose-dependent manner, to mismatched dsRNA in the clonogenic assay. Mismatched dsRNA was effective in inhibiting tumor growth (p less than 0.001) in nude mouse xenografts, with regression of the tumor mass seen in all animals. A significant increase in survival (p less than 0.001) was seen in the mismatched dsRNA treated group. In contrast, IFN-alpha did not inhibit tumor growth in vivo, even though significant titers of IFN-alpha (greater than 3,000 IRU/ml) were found in the serum shortly after treatment. Mismatched dsRNA did not induce the production of human IFNs by the tumor cells in vitro. Assays of mouse IFN induction and their in vitro antigrowth effects indicated that the in vivo antiproliferative effect of mismatched dsRNA was probably not due to potentiation of any direct effects by the induced mouse IFNs. Tumor growth inhibition appeared to occur, at least in part, from the significant augmentation (p less than 0.01) of natural killer cell activity by mismatched dsRNA, as measured in the spleen cells of treated mice. These results suggest that, although both IFN-alpha and mismatched dsRNA can be directly antiproliferative against this tumor, either the IFN-independent antitumor effects of mismatched dsRNA or the mismatched dsRNA-induced augmentation of the host immune response plays a major role in tumor regression. Potentially, both mechanisms may be important in this system.