Emergent synergistic lysosomal toxicity of chemical mixtures in molluscan blood cells (hemocytes).

The problem of effective assessment of risk posed by complex mixtures of toxic chemicals in the environment is a major challenge for government regulators and industry. The biological effect of the individual contaminants, where these are known, can be measured; but the problem lies in relating toxicity to the multiple constituents of contaminant cocktails. The objective of this study was to test the hypothesis that diverse contaminant mixtures may cause a greater toxicity than the sum of their individual parts, due to synergistic interactions between contaminants with different intracellular targets. Lysosomal membrane stability in hemocytes from marine mussels was used for in vitro toxicity tests; and was coupled with analysis using the isobole method and a linear additive statistical model. The findings from both methods have shown significant emergent synergistic interactions between environmentally relevant chemicals (i.e., polycyclic aromatic hydrocarbons, pesticides, biocides and a surfactant) when exposed to isolated hemocytes as a mixture of 3 & 7 constituents. The results support the complexity-based hypothesis that emergent toxicity occurs with increasing contaminant diversity, and raises questions about the validity of estimating toxicity of contaminant mixtures based on the additive toxicity of single components. Further experimentation is required to investigate the potential for interactive effects in mixtures with more constituents (e.g., 50-100) at more environmentally realistic concentrations in order to test other regions of the model, namely, very low concentrations and high diversity. Estimated toxicant diversity coupled with tests for lysosomal damage may provide a potential tool for determining the toxicity of estuarine sediments, dredge spoil or contaminated soil.

Failure of splanchnic resuscitation in the acutely injured trauma patient correlates with multiple organ system failure and length of stay in the ICU.

INTRODUCTION: The purpose of our study was to evaluate the relationship between the state of splanchnic perfusion and morbidity and mortality in the hemodynamically unstable trauma patient acutely resuscitated in the ICU. METHODS: Gastric intramucosal pH (pHi) was monitored in a blinded fashion in 19 consecutive critically ill trauma patients with evidence of systemic hypoperfusion (arterial pH [pHa] <7.35, base excess >2.3 mmol/L, lactic acid >2.3 mEq/L) who received right heart catheters to guide resuscitation and subsequent hemodynamic monitoring. DESIGN: Prospective randomized consecutive series with retrospective analysis of data. SETTING: University hospital, surgical ICU. RESULTS: The mean values of APACHE II (acute physiology and chronic health evaluation) Injury Severity Score, pHa, arterial base excess, cardiac index, oxygen delivery index, and oxygen consumption index by 24 h were similar (Student's t test, p>0.1) between survivors and nonsurvivors and between those who developed at most a single (SOF) vs multiple organ system failure (MOSF). Supranormal oxygen delivery and utilization parameters were evenly distributed among survivors and nonsurvivors and patients with SOF and MOSF (chi2, p>0.5). Ten patients had a pHi <7.32 and nine patients had a pHi > or = 7.32 by 24 h. Fifty percent of patients with a pHi <7.32 died, compared with 11% of patients with a pH > or = 7.32 (chi2, p=0.07). Sixty percent of patients with a pHi <7.32 developed MOSF compared with 11% of patients with a pHi > or = 7.32 (chi2, p=0.03). The one patient who developed MOSF and died in the pHi > or = 7.32 cohort suffered from massive head trauma and had all futile medical interventions halted. No other patients who achieved a pH > or = 7.32 by hour 24 developed MOSF. Survivors with a pHi <7.32 at hour 24 had an increased ICU stay (pHi <7.32=46+/-15 days, pHi > or = 7.32=13+/-9 days; p<0.01). A pHi <7.32 carried a relative risk of 4.5 for death and 5.4 for the occurrence of MOSF. CONCLUSION: Attainment of a pHi > or = 7.32 at hour 24 carried a significantly reduced likelihood of MOSF. Being an inference of the state of regional perfusion, in a high-risk microvascular bed, gastric intraluminal tonometry should identify perfusion states of compensated or uncompensated shock during hemodynamic resuscitation of the critically ill injury patient. A low pHi appears to be a marker of postresuscitative morbidity and subsequent increased length of stay.

Management of paroxysmal atrioventricular nodal reentrant tachycardia in the critically ill surgical patient.

OBJECTIVES: Paroxysmal atrioventricular nodal reentrant tachycardia is an infrequently encountered supraventricular arrhythmia that continues to present difficult management problems in the critically ill surgical patient. The purpose of this study was to evaluate the efficacy of a new treatment algorithm involving the sequential administration of different classes of antiarrhythmic agents until conversion to sinus rhythm was achieved. DESIGN: Nonrandomized, consecutive, protocol-driven descriptive cohort. SETTING: University hospital surgical and trauma intensive care unit (ICU). PATIENTS: During an 11-month period, we prospectively evaluated all hemodynamically stable patients who sustained new-onset atrioventricular nodal reentrant tachycardia. INTERVENTIONS: Vagal maneuver, followed by the rapid, sequential infusion of antiarrhythmic agents (i.e., adenosine, verapamil, and esmolol, respectively) until the arrhythmia was terminated. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients (4% of all admissions) were evaluated, including 16 trauma patients (injury Severity Score of 20 +/- 8) and 11 general surgical patients (Acute Physiology and Chronic Health Evaluation II score of 17 +/- 7). Time from ICU admission to onset of atrioventricular nodal reentrant tachycardia was 4.5 +/- 5 days (median 2.5). Arrhythmia termination was achieved in all patients within minutes (mean 13 +/- 10 [SD]). Incremental sequential adenosine administration alone, however, was successful in affecting conversion to sinus rhythm in only 44% of initial episodes of atrioventricular nodal reentrant tachycardia (95% confidence interval 21% to 67%). A total of 14 (52%) patients developed 38 relapses of paroxysmal supraventricular tachycardia in the ICU after initial conversion to sinus rhythm. These relapses required additional antiarrhythmic therapy. Adenosine was only effective in 34% of the relapses (95% confidence interval 17% to 53%). Seven (50%) of these 14 patients developed multiple relapses. However, only two patients were receiving suppressive calcium-channel or beta-adrenergic receptor blockade at the time of relapse. CONCLUSIONS: The use of a multiagent algorithm was effective for the initial conversion of new-onset atrioventricular nodal reentrant tachycardia to sinus rhythm in critically ill surgical and trauma patients. This preliminary report suggests that adenosine has marginal efficacy in the critically ill surgical or trauma patient. Given the high frequency of relapses, regardless of the agents used to achieve initial control, suppression therapy for the arrhythmia during the period of maximal cardiovascular stress is essential.

A method for predicting proportions of affected herds from proportions of affected animals.

The frequency of herds affected with 13 different diseases is shown to bear a simple relationship to the frequency of affected animals. The relationship seems to be useful for predicting proportions of affected herds.