Metformin-associated lactic acidosis following acute kidney injury. Efficacious treatment with continuous renal replacement therapy.

INTRODUCTION: Metformin is a biguanide anti-hyperglycaemic drug. Metformin-associated lactic acidosis may sometimes be life-threatening. Continuous renal replacement therapy has been suggested as a method for resolving this extremely dangerous metabolic state. We describe the history of six patients admitted to the intensive care unit over a 28-month period in pre-shock conditions because of severe lactic acidosis, attributed to metformin-associated lactic acidosis, and successfully treated. METHODS: We reviewed the charts of six patients admitted to our intensive care unit between January 2008 and May 2010. After initial assessment, all patients were treated with continuous renal replacement therapy. Admission serum lactate and creatinine levels, pH, need for ventilatory and cardiovascular support, as well as continuous renal replacement therapy details and length of stay were reviewed. RESULTS: Admission pH levels of the six patients ranged between pH 6.63 and 7.0 and their serum lactate levels ranged between 12 and 27 mmol/l; the estimated creatinine clearance ranged between 6 and 24 ml min(-1) 1.73 m(-2) . All patients required vasoactive support and five required ventilatory support. Lactate levels decreased to near zero with continuous renal replacement therapy within 7-19 h in five of the patients whose intensive care unit length of stay ranged between 1 and 5 days. One patient's length of stay reached 11 days because of pneumonia, one died from multi-organ failure and another suffered permanent neurological damage following prolonged cardiopulmonary resuscitation before continuous renal replacement therapy was administered. All other patients recovered without sequellae. CONCLUSIONS: Accurate recognition of metformin-associated lactic acidosis and prompt initiation of haemodialysis are paramount steps towards rapid recovery. Large series reports and controlled studies may better determine the optimal duration and best dialysis technique in these patients.

Contactless respiratory and heart rate monitoring: validation of an innovative tool.

PRIMARY OBJECTIVE: To assess the accuracy of the EverOn™ piezoelectric sensor based contactless heart rate and respiration rate monitoring system. METHODS: Measurements of the EverOn™ and reference devices were performed in a sleep lab and an intensive care unit (ICU) setting. One minute measurements by both the reference device and the EverOn™ were averaged and compared. Accuracy was defined in accordance with industry criteria. RESULTS: Respiration rate (RR) accuracy in the 41 children and 16 adults evaluated in the sleep lab was 93.1% and 90.6% respectively, and heart rate (HR) accuracy was 94.4% and 91.5% respectively. For the 42 ICU patients RR accuracy was 82.0% and 75% (versus end-tidal CO(2) and manual respectively), while accuracy of HR was 94.0%. The EverOn™ was found to be superior to the impedance technique in measuring RR. CONCLUSIONS: The system described was found to be accurate in accordance with regulatory and industry criteria.

Non-collision injuries in public buses: a national survey of a neglected problem.

OBJECTIVES: This prospective, nationally representative, multi-centre study was undertaken to assess non-collision injuries sustained by public bus passengers in Israel. METHODS: The emergency departments (EDs) of six medical centres, which participated in this eight month study, were chosen to represent both urban and rural catchment areas. All patients diagnosed with injuries sustained on a public bus not involved in a road traffic accident were promptly evaluated for mechanism and nature of injury and demographic parameters. RESULTS: The study cohort consisted of 120 patients (86 were female, 34 were male, age range 3-89 years). Over half were older than 55 years. The most common injuries were to the limbs, vertebral column, and head. The major mechanism of injury was acceleration/deceleration. Most patients were standing when they sustained the injuries. There were no fatalities, and 17 patients were admitted to hospital (9 of 17, 52% older than 55 years). Extrapolation to yearly national statistics suggests a probable total of 729 such injuries. CONCLUSION: The significant injuries inflicted on passengers of public buses not involved in road traffic accidents warrant decisive preventative measures by transportation authorities.

Envenomation by Trachinus draco in the eastern Mediterranean.

Injuries caused by weever fish ( spp) are probably more ubiquitous than reported. Such injuries are extremely painful and require prompt treatment. Only relatively few clinical descriptions of envenomation have been published. We present three patients with envenomation and describe their treatment. Two patients were fishermen injured while handling caught fish and one was a tourist wading into the sea for pleasure. The clinical picture was dominated by extreme pain, which responded partly to the application of warm water, and usually necessitated systemic opiates for adequate control. Follow-up in one of the patients indicated prolonged, slow recovery of the local inflammatory reaction. Prompt analgesia is the mainstay of treatment of this non-lethal but extremely painful envenomation, with the application of hot water being effective, although not always completely.

Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure.

OBJECTIVE: To test the efficacy of the molecular adsorbent recycling system (MARS) in patients with acute exacerbation of chronic liver disease. DESIGN: A prospective case analysis. SETTING: A university-affiliated tertiary medical center. PATIENTS AND METHODS: We applied MARS to treat a consecutive series of eight patients with acute exacerbation of chronic liver disease. RESULTS: The overall survival rate was 62.5%. All patients demonstrated improvement with regard to their degree of encephalopathy. In three patients, intracranial pressure and jugular bulb oxygen saturation decreased and cerebral perfusion pressure increased after treatment institution. Patients' hyperdynamic state was attenuated, as demonstrated by elevation of systemic vascular resistance, mean arterial pressure, and parallel reduction in cardiac index. A prompt reduction in serum ammonia, bilirubin, and lactate levels was observed. There were no complications during the treatment period. CONCLUSIONS: Applying MARS treatments to patients with acute exacerbation of chronic liver disease can detoxify blood, improve cerebral circulation, and reduce brain edema, as reflected by the reduction in intracranial pressure and jugular bulb oxygen saturation values in our patients. A partial reversal of the characteristic hyperdynamic circulation was also achieved. Despite our encouraging results, further testing is needed to determine the reliability of the system.

Antagonization of TNF attenuates systemic hemodynamic manifestations of envenomation in a rat model of Vipera aspis snakebite.

OBJECTIVES: Tumor necrosis factor (TNF) has been reported as a mediator of local tissue injury following snake envenomation in an intact rat model. We investigated whether systemic release of TNF occurs following Vipera aspis envenomation. We further analyzed the possible connection between envenomation-related hemodynamic depression and TNF antagonization (TNF antibodies or soluble TNF receptor). DESIGN: A prospective, randomized, controlled experimental study using a rat model for snake envenomation. SETTINGS: A medical university hospital research laboratory. INTERVENTION: Eighty rats (300-400 g) were divided into four groups (n = 20): control and three experimental groups. Intramuscular injection of V. asis 500 microg/kg was administered to the three experimental groups: venom only (group 1), venom and 40 microg anti-TNF antibodies (group 2), venom and 250 microg soluble TNF receptor (p55-R; group 3). Hemodynamic parameters were monitored up to 4 h following venom injection. MEASUREMENTS AND RESULTS: A significant hemodynamic deterioration (reduction in heart rate and blood pressure) occurred 30 min following venom injection in group 1 compared to groups 2 and 3, where hemodynamic parameters remained stable throughout the 4 h observation period. Serum levels of TNF were detected 15 min after venom injection and peaked after 2 h at 485+/-12 pg/ml. CONCLUSIONS: The hemodynamic consequences of intramuscular injection of V. aspis venom can be blunted in a rat by systemic antagonization of TNF activity prior to venom injection. The poisonous hemodynamic effects of the V. aspis venom might be caused by systemic release of TNF.

Liver support systems.

In recent years liver transplantation was shown to be the only clinically effective method of treating acute or chronic hepatic failure due to various causes. However, this ultimate therapeutic approach is limited by the growing disparity between organ donation and the number of patients on the waiting list. Factors such as high cost, morbidity, and the need for lifelong immunosuppression accelerated the research on alternative methods to support the failing liver. Recently, new technologies incorporating hepatocytes and extracorporeal circulation devices were introduced for liver support. This review presents current knowledge on liver support systems and their role in the treatment of acute liver failure.

An international training program to assist with establishing emergency medicine in Ethiopia.

Ethiopia has a population of 56 million and an area of 1,110,000 km(2). Ethiopia is one of the poorest nations in the world, and its health services system reflects that poverty. Accidental injury, violence, infectious diseases, and natural and manmade disasters abound, yet emergency medicine is practically nonexistent. Poorly equipped and staff emergency "rooms" supply substandard service even in the capital. Significant work and planning are under way by a group of high-quality and dedicated local physicians and nurses with international support from Israel and the United States. A coherent plan is due at the end of the year. Much financial and professional support from outside sources will be required for significant advances in the quality of emergency care to improve. Human as well are material resources are vital.

Xanthine oxidase and tumor necrosis factor alpha: possible mediators of remote tissue injury after viper envenomation.

BACKGROUND: Tumor necrosis factor is associated with various local and systemic inflammatory sequelae following snakebite. Xanthine oxidase is a principal mediator of remote tissue injury (e.g., lungs, heart, liver). OBJECTIVE: To investigate in a snakebite-like animal model the as yet unexplored role of TNF and XO in mediating organ damage following snakebite. METHODS: Sprague-Dawley rats were injected intramuscularly with a non-lethal 500 micrograms/kg dose of Vipera aspis venom (n = 10) or saline (n = 10). Blood pressure and heart rate were continuously monitored, TNF-alpha was measured in the blood, and total XO + xanthine dehydrogenase activity was assessed in various tissues. Lung histology and permeability indices were analyzed. RESULTS: Venom injection caused a significant (P < 0.05) reduction in both heart rate and invasive arterial pressure. The blood circulating TNF levels were significantly higher in the intoxicated group (P < 0.05 vs. saline group), with changes seen at 30 minutes from intoxication in both groups. Total XO + XDH activity in the kidney, lung and liver of the venom-injected group was significantly (P < 0.05) higher than in the saline group, while the activity in the heart was similar. CONCLUSIONS: The mediation of remote organ and hemodynamic changes following intramuscular injection of a non-lethal dose of Vipera aspis venom can be attributed partly to TNF and partly to XO. More research is needed to better understand the role of either compound and the time frame of their activity before specific antagonists can be introduced for snakebite management.

Epidemiology of ceftazidime-resistant Klebsiella pneumoniae in a large university hospital in Tel Aviv.

BACKGROUND: An increase in multiple drug-resistant Klebsiella pneumoniae due to extended spectrum beta-lactamase production has recently been reported from many centers around the world. There is no information in the literature regarding this problem in Israel. A high prevalence of ceftazidime-resistant K. pneumoniae was noted in our Intensive Care Unit in the first few months of 1995. OBJECTIVE: To describe the epidemiology of ceftazidime-resistant K. pneumoniae in our medical center, as representing the situation in tertiary care hospitals in Israel. METHODS: We vigorously restricted the use of ceftazidime in the ICU and enforced barrier precautions. The susceptibility rate of K. pneumoniae was surveyed in the ICU and throughout the hospital before and after the intervention in the ICU. RESULTS: Following the intervention, the susceptibility rate of K. pneumoniae increased from 11% (3/28) to 47% (14/30) (P < 0.01) among ICU isolates, from 55% (154/280) to 62% (175/281) (P = 0.08) among total hospital isolates, and from 61% (50/82) to 74% (84/113) (P < 0.05) among total hospital blood isolates, although no additional control measures were employed outside the ICU. CONCLUSIONS: The epidemiology of ceftazidime-resistant K. pneumoniae in our medical center is similar to that reported from other centers around the world. Early awareness to the emergence of this resistance, identification of the source of the epidemic, and prompt action at the putative source site may reduce the rate of acquisition and spread of such resistance inside and outside of the source unit.

Kerosene-induced severe acute respiratory failure in near drowning: reports on four cases and review of the literature.

OBJECTIVE: The purpose of this study is to present an unusual respiratory and cardiovascular course after intoxication and near drowning in a river contaminated with kerosene. DESIGN: Case reports and review of the literature. SETTING: Intensive care unit of a university-affiliated hospital. PATIENTS: Four patients after near drowning. INTERVENTION: Supportive only. RESULTS: The four patients developed acute respiratory failure. Cardiomyopathy was present in three patients and a persistent hypokalemia in two patients. The onset of the symptoms was delayed, which led to underestimation of the severity of their illness. Two of the four patients died. The diagnosis of hydrocarbon intoxication was based on bronchoalveolar lavage results, neutrophilic alveolitis with the presence of lipid-laden macrophages, and evidence of lipoid pneumonia from the autopsy performed on one victim. One patient who clinically deteriorated and another who developed a severe restrictive pulmonary disorder were treated with corticosteroids, which were effective only in the latter patient. CONCLUSIONS: Acute kerosene intoxication in a near-drowning event often results in severe respiratory and cardiac failure, with a high fatality rate. Treatment with corticosteroids may lead to a rapid improvement in lung function.

Cross-sensitivity between isoflurane and diazepam: evidence from a bidirectional tolerance study in mice.

We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity to diazepam. Mice were divided into four groups: group 1, treated with diazepam, 10 mg/kg i.p. twice daily; group 2, vehicle-treated controls; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (HWT). All control mice but only 10% of the diazepam-treated mice failed the HWT. Groups 1 and 2 were then exposed to increasing concentrations of isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7+/-0.7%, compared with 0.6+/-0.1% in controls (group 2) (P<0.001); the ED50 was 0.75% vs. 0.65%. Group 1 mice lost the righting reflex at 0.94+/-0.07% isoflurane vs. 0.87+/-0.06% in group 2 (P<0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175+/-161 s in group 1 vs. 343+/-275 s in group 2 (P<0.02). Twenty-four hours after the last of the repeated exposures to isoflurane, we examined the responses of groups 3 and 4 to increasing concentrations of isoflurane. Mice in group 3 lost the righting reflex at 1.0+/-0.06% isoflurane vs. 0.9+/-0.04% in controls (group 4) (P<0.001); the ED50 was 0.96% vs. 0.85%. Recovery time was 113+/-124 s vs. 208+/-126 s in groups 3 and 4 (P<0.09). Diazepam, 3 mg/kg i.p. administered to groups 3 and 4, caused loss of the HWT reflex in 33% of group 3 mice and in 82% of controls (group 4) (P<0.001). It appears that prolonged exposure to both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.

[Severe heat stroke in an intensive care unit: course of the disease in the intensive care unit, and early and subsequent treatment results].

During the August 1998 heat wave in Tel Aviv we admitted many patients for acute heat-related illness; 6 had severe heat stroke and were admitted in critical condition. We describe their clinical courses during the first 5 days of hospitalization, including response to treatment and implications for future management of this disorder. The mean APACHE II score of the 6 was 30 +/- 3.5 and mean Glasgow Coma Scale rating 3.5 +/- 0.5; they were in hypovolemic shock and respiratory failure, necessitating mechanical ventilation. Despite early effective therapy (core temperature in all was reduced to less than 39 degrees C in less than 1 hour), there was 1 death (mortality 15%) and 4 required further intensive care for life-threatening multiple organ failure. During severe heat waves a significant number of referrals for acute heat-related illness must be anticipated, possibly overwhelming admission capacity of regional intensive-care units. Severe heat stroke complicated by multi-organ failure is not necessarily related to prior physical activity. Although important in determining prognosis, early treatment does not prevent severe complications. Mechanisms regulating body heat may remain disturbed for days following early treatment and apparent stabilization, mandating continued hospitalization.

[Injuries due to falls in urban buses: 100 consecutive cases].

We reviewed the charts of 100 consecutive emergency department (ED) cases of injuries in public buses (not due to actual traffic accidents) seen during 7 months in 1995. There were 29 males and 71 females with a mean age of 55.6 +/- 21.4 years, median 60, and range 13-91. 92 were discharged home directly from the ED. 3 were admitted to general surgical wards, and 1 each to the orthopedic, medical and neurosurgical wards, while 2 soldiers were sent for observation to a military clinic. There were 28 spinal column, 27 head and 25 chest injuries; 1 patient died. There were no significant differences in admissions during the months of the year. 58% of injuries occurred during normal working hours, with a peak incidence at about 1000 hrs. The most common cause was falling while standing, due to sudden acceleration/deceleration or sharp turns. There are 1900 buses in Tel Aviv which carry 1.1 million passengers daily and most of which are capable of significant acceleration. A high proportion of passengers travel standing, and elderly passengers are more liable to fall when the bus accelerates, decelerates or turns. We calculate a potential national yearly bus injury toll from falls of more than 1000, which often result in significant morbidity and even mortality. A national survey is now being planned.

Neutrophilia of infection/inflammation: are we really dealing with "inflamed" leukocytes?

We adopted whole blood flow cytometry and direct labeling of the CD11b/CD18 and CD62L antigens to study the relationship between their expression and leukocytosis in patients with infection/inflammation, acute stress and healthy volunteers. Mean +/- S.D. channel fluorescence intensity of CD11b/CD18 antigen on peripheral blood polymorphonuclears did not differ between patients with infection/ inflammation (173+/-78) and controls (167+/-72), but was significantly (p = 0.04) reduced in stress (135+/-60). No correlation was found between CD11b/CD18 antigen level and either polymorphonuclears absolute number or serum C-reactive protein. A significant negative correlation was noted between CD62L antigen expression on polymorphonuclears and their absolute number. We assume that cells with increased CD11b/CD18 surface concentrations are retained in the capillaries and that part of the leukocytes in the peripheral blood are stressed leukocytes with reduced CD11b/CD18. Thus, leukocytes detected in peripheral blood are not necessarily the most "inflamed" ones.

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.

Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock.

We examined the kinetics of shedding of the soluble TNF receptors (TNF-Rs) in response to TNF leakage during isolated limb perfusion procedures and correlated them to the resulting hemodynamic effects. Shedding of the TNF-Rs started 7 min after TNF leakage into the systemic circulation. Three waves of shedding were observed peaking at 1, 8-12, and 48-72 h both in vivo and in cell cultures. The soluble receptors prolonged the half-life of TNF in the systemic circulation to 2.5-6 h. Excess shedding of the p75 compared with p55 TNF-Rs was noted during the first wave. The amount and speed of shedding of the p75 TNF-Rs were proportional to the serum TNF levels (P < 0.001). A maximal shedding capacity was attained only during the first wave of shedding, at TNF concentrations of approximately 1.5 ng/ml. Above this level, the linearity between TNF and its soluble receptors was lost. TNF-induced hypotension coincided with the initial imbalance between the concentrations of TNF and its soluble receptors. Despite the spontaneous correction of this imbalance at 8-12 h, the hemodynamic and biochemical alterations persisted and were further aggravated at 18 h, suggesting that other factors induced earlier by TNF are responsible for the perpetuation of the hemodynamic instability. This study may provide the basis for a more physiological therapeutic approach to TNF neutralization in septic shock patients.

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.

A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose.

The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to 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 0.3 mg 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 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 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 2 mg bolus, approximately equal to 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 to carbamazepine or whose ECG shows abnormalities typical to 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.