Valery Rudick

Practical Guidelines for Acute Care of Victims of Bioterrorism: Conventional Injuries and Concomitant Nerve Agent Intoxication

THE potential use of weapons of mass destruction has recently become a real threat even in regions of the world that are remote from areas of ongoing armed conflicts. Episodes of the use of sarin or VX, both potent acetylcholinesterase (AChE) inhibitors that cause cholinergic crisis, in the terrorist attacks against civilians in Japan in 1994 and 1995 which produced several fatalities and hundreds of casualties, 1,2 and the military use of nerve agents (NA) by Iraq against Iran and the Kurdish population during the 1980s are grim examples of the deadly potential of NA. Victims of a mass casualty event can suffer from physical trauma alone or from trauma in combination with gas intoxication. The exposure of a physically injured patient to a toxic substance, in a scenario of mass injury, has recently gained major attention among planners of future protocols for emergency medical services. 3 Furthermore, when a civilian population becomes the prime target of an NA attack, diversity in age and previous health status are expected to increase the extent of the injuries compared with those of healthy adult soldiers by as much as 10-fold. 4 Because rapid deterioration and multiorgan involvement are to be expected after a physically injured individual is exposed to a toxic substance, proper organization and complex but efficient acute medical and surgical care systems must be organized and deployed to ensure a maximal number of saved lives. The various national rescue forces that have traditionally been tasked with models of rapid evacuation and decontamination of large numbers of poisoned civilians from affected areas appear to be only a fraction of future necessities. 5 The proposed management of mass casualty events needs to be based on triage principles and acute care measures. These should include: rapid identification of the offending agent, swift decontamination by wellprotected emergency medical personnel, and triageguided mass evacuation to a nearby medical facility that should be well equipped and staffed with personnel who have been properly trained to deal with such multifaceted events.

Soluble tumor necrosis factor receptors reduce bowel ischemia-induced lung permeability and neutrophil sequestration

OBJECTIVES To evaluate the possible role of tumor necrosis factor (TNF) in the development of lung injury after bowel ischemia, and the ability of TNF-soluble receptors to negate TNF toxicity, using a rat small bowel ischemia and reperfusion model. DESIGN Prospective, randomized, controlled laboratory study. SETTING Research laboratory. SUBJECTS Forty adult male Sprague-Dawley rats weighing approximately 300 g. INTERVENTIONS The rats were divided equally into four groups: a) ischemia and reperfusion alone; b) those animals receiving TNF antibodies (1 mL) before reperfusion; and c) those animals receiving 200 micrograms of human recombinant TNF soluble receptors. These 30 anesthetized rats underwent 60 mins of superior mesenteric artery occlusion per 4 hrs of reperfusion. The remaining ten animals were sham operated (laparotomy), serving as controls. Lung permeability was measured using bovine serum albumin labeled with 125I, and organ injury was assessed histologically. MEASUREMENTS AND MAIN RESULTS Thirty and 60 mins after declamping and reperfusion, plasma TNF concentrations increased to 830 +/- 66 and 173 +/- 56 pg/mL, respectively, compared with 10 pg/mL before ischemia (p < .001). In sham-operated control rats, TNF concentrations did not increase from baseline concentrations. Four hours after reperfusion, sequestration of neutrophils in the pulmonary microcirculation was noted (319 +/- 60 vs. 84 +/- 13 neutrophils/10 high-power fields in sham-operated rats [p < .04]). Pulmonary microvascular leak also occurred, as measured by translocation of radiolabeled albumin into the bronchoalveolar space and expressed as the ratio of bronchoalveolar lavage to blood concentrations. This ratio was 5.3 +/- 0.8 in ischemic control animals compared with 1.1 +/- 0.3 in sham animals (p < .03). Treatment with antibodies to TNF before reperfusion attenuated the pulmonary injury (75 +/- 6 neutrophils/10 high-power fields, permeability index 1.6 +/- 0.1) less than in ischemic controls (p < .005). A similar protection was achieved with soluble TNF receptors, which prevented bowel ischemia-induced lung neutrophil sequestration (117 +/- 35 neutrophils/10 high-power fields, pulmonary vascular leak ratio of 2.3 +/- 0.1, p < .05). CONCLUSIONS The results of this study show that ischemia and subsequent reperfusion of the intestine in rats produce lung injury. This injury is mediated, at least in part, by TNF. Soluble TNF receptors are an effective tool in preventing lung TNF injury after intestinal ischemia.

A Risk-Benefit Assessment of Flumazenil in the Management of Benzodiazepine Overdose

SummaryThe worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to an increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 µg/kg is effective in neonates and small children. Intramuscular, oral (20 to 25mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2mg bolus, ≈1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable.The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate or carbamazepine or whose ECG shows abnormalities typical of those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia.Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.

Multiple organ dysfunction after remote circulatory arrest: common pathway of radical oxygen species?

OBJECTIVES Cardiovascular, respiratory, and vascular dysfunction can follow trauma-induced no-flow-reflow states: hemorrhage, blunt trauma, or neurogenic shock. Liver ischemia-reperfusion (IR) induces remote lung damage by means of xanthine oxidase (XO) pro-oxidant activity. This damage was not proven in the heart, neither was the independent role of radical oxygen species (ROS) established in such cases. We investigated whether multiple organ dysfunction after a trauma-like IR is XO and ROS related and whether clinically used ROS scavengers could be beneficial. METHODS A controlled, randomized trial in which isolated rat livers, hearts, lungs, and aortic rings were perfused with Krebs-Henseleit solutions. After stabilization, livers were either perfused or made ischemic (2 hours). Then, pairs of liver plus heart, lung, or ring were reperfused in series (15 minutes), and then the second organ circulated alone for 45 minutes. Remote organ protection against the pro-oxidant hepatic-induced toxicity was evaluated by using allopurinol (1 mmol/L, heart), mannitol (0.25 g/kg, lung), or methylene blue (40 mg/kg, ring). RESULTS IR liver effluents typically contained high lactate dehydrogenase, XO, and uric acid concentrations compared with control organs. IR was associated with doubled lung peak inspiratory pressure and reduced static compliance. Myocardial velocity of contraction and relaxation decreased by one third of baseline, and rings contracted abnormally and responded inadequately to phenylephrine. Wet-weight to dry-weight ratios in the remote organs increased as well. Most remote reperfusion injuries were attenuated by the drugs. CONCLUSION Liver no-flow-reflow directly induces myocardial, pulmonary, and vascular dysfunction. These are likely mediated by XO and ROS. The tested drugs protected against these pro-oxidants, even in the presence of circulating XO.

Antichemical protective gear prolongs time to successful airway management: A randomized, crossover study in humans

BackgroundAirway management is the first step in resuscitation. The extraordinary conditions in mass casualty situations impose special difficulties in airway management, even for experienced caregivers. The authors evaluated whether wearing surgical attire or antichemical protective gear made any difference in anesthetists’ success of airway control with either an endotracheal tube or a laryngeal mask airway. MethodsFifteen anesthetists with 2–5 yr of residency and wearing either full antichemical protective gear or surgical attire intubated or inserted laryngeal masks in 60 anesthetized patients. The study was performed in a prospective, randomized, crossover manner. The duration of intubation/insertion was measured from the time the device was grasped to the time a normal capnography recording was obtained. ResultsEndotracheal tubes were introduced significantly (P < 0.01) faster when the anesthetist wore surgical attire (31 ± 7 vs. 54 ± 24 s for protective gear), but the mean times necessary to successfully insert laryngeal masks were similar (44 ± 20 s for surgical attire vs. 39 ± 11 s for protective gear). Neither performance failure nor incidences of hypoxemia were recorded. ConclusionsThis first report in humans shows to what extent anesthetists’ wearing of antichemical protective gear slows the time to intubate but not to insert a laryngeal mask airway compared with wearing surgical attire. Laryngeal mask airway insertion is faster than tracheal intubation when wearing protective gear, indicating its advantage for airway management when anesthetists wear antichemical protective gear. If chances for rapid and successful tracheal intubation under such chaotic conditions are poor, laryngeal mask airway insertion is a viable choice for airway management until a proper secured airway is obtainable.

Permissive hypercapnia ventilation in patients with severe pulmonary blast injury.

OBJECTIVES To describe our experience with the use of limited peak inspiratory pressure (PIP), volume-controlled ventilation, and permissive hypercapnia in patients with severe pulmonary blast injury. METHODS Patients with pulmonary blast injury were ventilated using volume-controlled, synchronized intermittent mandatory ventilation. Whenever PIP exceeded 40 cm H2O, the tidal volume was decreased to maintain PIP at less than 40 cm H2O. Whenever the arterial pH fell below 7.2, the ventilator rate was increased in increments of 2 breaths per minute until the arterial pH rose to 7.25. RESULTS Between 1994 and 1996, 17 patients with severe pulmonary blast injury (10 from enclosed space explosions and seven from open space ones), requiring mechanical ventilatory support were admitted to our intensive care unit. Four patients developed increasing PaCO2 levels (to 93 +/- 12 mm Hg) associated with the reduction in arterial pH that was corrected by increasing the ventilator rate. There was evidence of ventilator-induced pulmonary barotrauma. Of the 17 patients, 15 patients (88%) survived. CONCLUSIONS Limited PIP in a volume-controlled ventilation is a useful and safe mode of mechanical ventilation in patients with pulmonary blast injury.

Administration of amphotericin B in lipid emulsion decreases nephrotoxicity : Results of a prospective, randomized, controlled study in critically ill patients

OBJECTIVES To evaluate the differences in efficacy and in clinical and biochemical tolerance to amphotericin B administered in a lipid emulsion compared with amphotericin B administered in 5% dextrose in water in the treatment of Candida albicans infection in intensive care unit (ICU) patients. DESIGN Prospective, controlled, randomized study, conducted during a 2.5-yr period, comparing the two treatment protocols. SETTING General ICU of a university-affiliated municipal hospital. PATIENTS Sixty consecutive critically ill patients with confirmed or suspected Candida infection. INTERVENTIONS Patients received amphotericin B (1 mg/kg/24 hrs), administered randomly in 5% dextrose in water (group A), or in lipid emulsion (20% intralipid) (group B). MEASUREMENTS AND MAIN RESULTS Clinical tolerance (fever, chills, hemodynamics), hepatorenal tolerance, and biological tolerance (serum electrolytes and coagulation profile) were evaluated. Patients receiving amphotericin B in lipid emulsion experienced a lower frequency rate of drug-associated fever (61.4% vs. 5.8%, p < .003) rigors (54% vs. 8.5%, p < .004), hypotension (17% vs. 0%), and nephrotoxicity (increase of serum creatinine concentration 66.7% vs. 20%, p < .0002). Significant (264,500 +/- 71,460 to 163,570 +/- 34,450 mm3, p < .01) thrombocytopenia, not associated with active bleeding, occurred in patients receiving amphotericin B lipid in emulsion but not in patients receiving the drug in dextrose. CONCLUSIONS Treatment with amphotericin B in a lipid emulsion when given to critically ill patients with Candida sepsis seems to be safer and as effective as the conventional mode of administration.

Lung preconditioning with N-acetyl-L-cysteine prevents reperfusion injury after liver no flow-reflow: a dose-response study.

Background. Circulating xanthine oxidase activity and the generated oxidants have been linked to lung reperfusion injury from no flow-reflow conditions in other organs after organ transplantation or surgery. N-acetyl-l-cysteine (NAC), an oxidant scavenger, promotes glutathione in its reduced form (GSH) that is depleted during ischemia. We have recently demonstrated its efficacy in protecting lungs from reperfusion injury if administered during reperfusion of postischemic liver. We now investigated whether preconditioning of lungs with NAC could attenuate lung respiratory or vascular derangement after no flow-reflow (ischemia-reperfusion, IR) and if this depends on lung GSH levels. Methods. Rat isolated livers were stabilized and perfused with modified Krebs-Henseleit solution (KH) (control, n=12) or made ischemic (no flow, IR-0, n=12) for 2 hr. Meanwhile, lungs were isolated, ventilated, and stabilized (KH+bovine albumin 5%). Serial perfusion (15 min) of liver+lung pairs took place followed by lung only recirculation (45 min) with the accumulated solution. Another three controls and three ischemic groups included lungs treated during stabilization with NAC at 100 mg·kg−1, 150 or 225 mg·kg−1 (in 2.5, 3.7 or 5.5 mmol solutions, respectively). Results. Ischemic liver damage, expressed by circulating hepatocellular constituents, was associated with pulmonary artery and ventilatory pressure increases by 70–100% of baseline, abnormal wet-to-dry weight ratio, and abnormal bronchoalveolar lavage volume and content in the IR-0 (nontreated) and the IR-100 and IR-225 pretreated lungs. NAC-150 pretreatment afforded preservation for most parameters. GSH content in the IR-150 lung tissue was only 11% higher than that of IR-225, but 2-fold that in IR-0 and IR-100 GSH lungs. Conclusion. Lung preconditioning with NAC prevents reperfusion injury but not in a dose-related manner. Although enhanced GSH tissue content explains lung protection, GSH-independent NAC activity is another possibility.

Direct Induction of Acute Lung and Myocardial Dysfunction by Liver Ischemia and Reperfusion

OBJECTIVES To investigate whether liver ischemia and reperfusion (IR) directly affect functions of remote organs. BACKGROUND Cardiovascular and respiratory dysfunction follows hemorrhage, spinal shock, or trauma as a result of no-flow-reflow phenomena. Hepatic IR induces remote organ damage probably by xanthine oxidase and oxygen species. MATERIALS AND METHODS Isolated rat livers, lungs, and hearts were perfused with Krebs-Henseleit solutions. After stabilization, livers were either perfused or made ischemic. Then, livers and hearts or livers and lungs were reperfused in series, and the liver was disconnected and the second organ continued to perfuse with the accumulated effluents. MEASUREMENTS AND MAIN RESULTS Ischemic and reperfused liver effluent contained high lactate dehydrogenase and uric acid concentrations compared with controls; xanthine oxidase increased 60 to 100 times. Ischemic and reperfused lung peak inspiratory pressure almost doubled; airway static compliance halved; myocardial contractility decreased to 70% of baseline; wet weight-to-dry weight ratios of lungs and livers increased. CONCLUSION Ischemic and reperfused liver can directly induce myocardial and pulmonary dysfunction, presumably by oxidant-induced injury.

Anaesthesia and critical care considerations in nerve agent warfare trauma casualties

Nerve agents (NA) (tabun, sarin, suman, VX) have been stocked around the world for some time and still present a major threat to civilian as well as to military populations. Since NA can be delivered through both an aerial spray system and a ballistic system, victims could suffer both NA intoxication and multiple trauma necessitating urgent surgical intervention followed by intensive care. These patients can be expected to be extremely precarious neurologically, respiratorily and haemodynamically. Moreover, their clinical signs can be misleading. Further exacerbating the problem is the fact that interactions of NA with the pharmacological agents used for resuscitation and/or during anaesthesia can aggravate organ instability even more and possibly cause systemic collapse. There are no protocols for perioperative critical care and early assessment or for the administration of anaesthesia for surgical interventions in such combined multiple trauma and intoxicated casualties. We propose a scheme for the administration of critical care and anaesthesia based on the scant anecdotal reports that have emerged after the occurrence of local accidents involving NA intoxication and on the neuropharmacological knowledge of the pesticide organophosphate poisoning database, these compounds being related chemical substances.