Tomas Drabek

The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials.

Background:Patients with sepsis syndrome commonly have low serum selenium levels. Several randomized controlled trials have examined the efficacy of selenium supplementation on mortality in patients with sepsis. Objective:To determine the efficacy and safety of high-dose selenium supplementation compared to placebo for the reduction of mortality in patients with sepsis. Sources of Data:We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SciFinder, and Clinicaltrials.gov. Selection Criteria:Randomized controlled parallel group trials comparing selenium supplementation in doses greater than daily requirement to placebo on the outcome of mortality in patients with sepsis syndrome. Data Collection and Analysis:Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcome was mortality; secondary outcomes were ICU length of stay, nosocomial pneumonia, and adverse events. Trial authors were contacted for additional or clarifying information. Results:Nine trials enrolling a total of 792 patients were included. Selenium supplementation in comparison to placebo was associated with lower mortality (odds ratio, 0.73; 95% CI, 0.54, 0.98; p = 0.03; I2 = 0%). Among patients receiving and not receiving selenium, there was no difference in ICU length of stay (mean difference, 2.03; 95% CI, –0.51, 4.56; p = 0.12; I2 = 0%) or nosocomial pneumonia (odds ratio, 0.83; 95% CI, 0.28, 2.49; p = 0.74; I2 = 56%). Significant heterogeneity among trials in adverse event reporting precluded pooling of results. Conclusions:In patients with sepsis, selenium supplementation at doses higher than daily requirement may reduce mortality. We observed no impact of selenium on ICU length of stay or risk of nosocomial pneumonia.

Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs.

Several laboratory studies suggested that induced hypothermia during hemorrhagic shock improves survival. Inhaled hydrogen sulfide (H2S) induced hypothermia and decreased metabolism in mice and rats but not in piglets. We tested the hypothesis that i.v. H2S will induce hypothermia, reduce oxygen consumption (VO2), and improve outcome in prolonged hemorrhagic shock in pigs. We also assessed markers of organ injury (alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, creatinine, and troponin) and level of protein thiols to monitor H2S metabolism. In a prospective randomized study, pigs were subjected to volume-controlled hemorrhagic shock with limited fluid resuscitation to maintain MAP 30 mmHg or greater. The study group received infusion of H2S at 5 mg·kg−1·h−1; the control group received vehicle (n = 8 per group). Dose was based on the highest tolerated dose in pilot studies. Full resuscitation was initiated after 3 h. There were no differences in survival at 24 h between groups (2/8 in H2S vs. 3/8 in control group). Heart rate increased similarly during hemorrhagic shock in both groups. Cardiac output was better preserved in the delayed phase of hemorrhagic shock in the control group. Temperature and VO2 were similar in both groups during hemorrhagic shock and resuscitation. Markers of organ injury and protein thiols markedly increased in both groups with no differences between groups. In conclusion, we were not able to demonstrate the hypothermia-inducing effect or a reduction in VO2 from H2S infusion in our model of hemorrhagic shock in pigs. Our data mirror those seen in piglets and provide additional evidence of difficulty in translating the hypothermia effect of H2S to large animals in a clinically relevant postinsult paradigm.

Induction of Profound Hypothermia for Emergency Preservation and Resuscitation Allows Intact Survival After Cardiac Arrest Resulting From Prolonged Lethal Hemorrhage and Trauma in Dogs

Background— Induction of profound hypothermia for emergency preservation and resuscitation (EPR) of trauma victims who experience exsanguination cardiac arrest may allow survival from otherwise-lethal injuries. Previously, we achieved intact survival of dogs from 2 hours of EPR after rapid hemorrhage. We tested the hypothesis that EPR would achieve good outcome if prolonged hemorrhage preceded cardiac arrest. Methods and Results— Two minutes after cardiac arrest from prolonged hemorrhage and splenic transection, dogs were randomized into 3 groups (n=7 each): (1) the cardiopulmonary resuscitation (CPR) group, resuscitated with conventional CPR, and the (2) EPR-I and (3) EPR-II groups, both of which received 20 L of a 2°C saline aortic flush to achieve a brain temperature of 10°C to 15°C. CPR or EPR lasted 60 minutes and was followed in all groups by a 2-hour resuscitation by cardiopulmonary bypass. Splenectomy was then performed. The CPR dogs were maintained at 38.0°C. In the EPR groups, mild hypothermia (34°C) was maintained for either 12 (EPR-I) or 36 (EPR-II) hours. Function and brain histology were evaluated 60 hours after rewarming in all dogs. Cardiac arrest occurred after 124±16 minutes of hemorrhage. In the CPR group, spontaneous circulation could not be restored without cardiopulmonary bypass; none survived. Twelve of 14 EPR dogs survived. Compared with the EPR-I group, the EPR-II group had better overall performance, final neurological deficit scores, and histological damage scores. Conclusions— EPR is superior to conventional CPR in facilitating normal recovery after cardiac arrest from trauma and prolonged hemorrhage. Prolonged mild hypothermia after EPR was critical for achieving intact neurological outcomes.

Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs

We have used a rapid induction of profound hypothermia (> 10°C) with delayed resuscitation using cardiopulmonary bypass (CPB) as a novel approach for resuscitation from exsanguination cardiac arrest (ExCA). We have defined this approach as emergency preservation and resuscitation (EPR). We observed that 2 h but not 3 h of preservation could be achieved with favorable outcome using ice-cold normal saline flush to induce profound hypothermia. We tested the hypothesis that adding energy substrates to saline during induction of EPR would allow intact recovery after 3 h CA. Dogs underwent rapid ExCA. Two minutes after CA, EPR was induced with arterial ice-cold flush. Four treatments (n = 6/group) were defined by a flush solution with or without 2.5% glucose (G + or G–) and with either oxygen or nitrogen (O + or O–) rapidly targeting tympanic temperature of 8°C. At 3 h after CA onset, delayed resuscitation was initiated with CPB, followed by intensive care to 72 h. At 72 h, all dogs in the O + G + group regained consciousness, and the group had better neurological deficit scores and overall performance categories than the O—groups (both P < 0.05). In the O + G—group, four of the six dogs regained consciousness. All but one dog in the O—groups remained comatose. Brain histopathology in the O—G + was worse than the other three groups (P < 0.05). We conclude that EPR induced with a flush solution containing oxygen and glucose allowed satisfactory recovery of neurological function after a 3 h of CA, suggesting benefit from substrate delivery during induction or maintenance of a profound hypothermic CA.

Global and regional differences in cerebral blood flow after asphyxial versus ventricular fibrillation cardiac arrest in rats using ASL-MRI

Both ventricular fibrillation cardiac arrest (VFCA) and asphyxial cardiac arrest (ACA) are frequent causes of CA. However, only isolated reports compared cerebral blood flow (CBF) reperfusion patterns after different types of CA, and even fewer reports used methods that allow serial and regional assessment of CBF. We hypothesized that the reperfusion patterns of CBF will differ between individual types of experimental CA. In a prospective block-randomized study, fentanyl-anesthetized adult rats were subjected to 8min VFCA or ACA. Rats were then resuscitated with epinephrine, bicarbonate, manual chest compressions and mechanical ventilation. After the return of spontaneous circulation, CBF was then serially assessed via arterial spin-labeling magnetic resonance imaging (ASL-MRI) in cortex, thalamus, hippocampus and amygdala/piriform complex over 1h resuscitation time (RT). Both ACA and VFCA produced significant temporal and regional differences in CBF. All regions in both models showed significant changes over time (p<0.01), with early hyperperfusion and delayed hypoperfusion. ACA resulted in early hyperperfusion in cortex and thalamus (both p<0.05 vs. amygdala/piriform complex). In contrast, VFCA induced early hyperperfusion only in cortex (p<0.05 vs. other regions). Hyperperfusion was prolonged after ACA, peaking at 7min RT (RT7; 199% vs. BL, Baseline, in cortex and 201% in thalamus, p<0.05), then returning close to BL at ∼RT15. In contrast, VFCA model induced mild hyperemia, peaking at RT7 (141% vs. BL in cortex). Both ACA and VFCA showed delayed hypoperfusion (ACA, ∼30% below BL in hippocampus and amygdala/piriform complex, p<0.05; VFCA, 34-41% below BL in hippocampus and amygdala/piriform complex, p<0.05). In conclusion, both ACA and VFCA in adult rats produced significant regional and temporal differences in CBF. In ACA, hyperperfusion was most pronounced in cortex and thalamus. In VFCA, the changes were more modest, with hyperperfusion seen only in cortex. Both insults resulted in delayed hypoperfusion in all regions. Both early hyperperfusion and delayed hypoperfusion may be important therapeutic targets. This study was approved by the University of Pittsburgh IACUC 1008816-1.

Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial.

Objectives:Extracorporeal cardiopulmonary resuscitation with cardiopulmonary bypass potentially provides cerebral reperfusion, cardiovascular support, and temperature control for resuscitation from cardiac arrest. We hypothesized that extracorporeal cardiopulmonary resuscitation is feasible after ventricular fibrillation cardiac arrest in rats and improves outcome versus conventional cardiopulmonary resuscitation. Design:Prospective randomized study. Setting:University laboratory. Subjects:Adult male Sprague-Dawley rats. Interventions:Rats (intubated, instrumented with arterial and venous catheters and cardiopulmonary bypass cannulae) were randomized to conventional cardiopulmonary resuscitation, extracorporeal cardiopulmonary resuscitation with/without therapeutic hypothermia, or sham groups. After 6 minutes of ventricular fibrillation cardiac arrest, resuscitation was performed with drugs (epinephrine, sodium bicarbonate, and heparin), ventilation, either cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation, and defibrillation. Temperature was maintained at 37.0°C or 33.0°C for 12 hours after restoration of spontaneous circulation. Neurologic deficit scores, overall performance category, histological damage scores (viable neuron counts in CA1 hippocampus at 14 days; % of sham), and microglia proliferation and activation (Iba-1 immunohistochemistry) were assessed. Measurements and Main Results:Extracorporeal cardiopulmonary resuscitation induced hypothermia more rapidly than surface cooling (p < 0.05), although heart rate was lowest in the extracorporeal cardiopulmonary resuscitation hypothermia group (p < 0.05). Survival, neurologic deficit scores, overall performance category, and surviving neurons in CA1 did not differ between groups. Hypothermia significantly reduced neuronal damage in subiculum and thalamus and increased the microglial response in CA1 at 14 days (all p < 0.05). There was no benefit from extracorporeal cardiopulmonary resuscitation versus cardiopulmonary resuscitation on damage in any brain region and no synergistic benefit from extracorporeal cardiopulmonary resuscitation with hypothermia. Conclusions:In a rat model of 6-minute ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation leads to survival with intact neurologic outcomes. Twelve hours of mild hypothermia attenuated neuronal death in subiculum and thalamus but not CA1 and, surprisingly, increased the microglial response. Resuscitation from ventricular fibrillation cardiac arrest and rigorous temperature control with extracorporeal cardiopulmonary resuscitation in a rat model is feasible, regionally neuroprotective, and alters neuroinflammation versus standard resuscitation. The use of experimental extracorporeal cardiopulmonary resuscitation should be explored using longer insult durations.

Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

Trauma patients who suffer cardiac arrest (CA) from exsanguination rarely survive. Emergency preservation and resuscitation using hypothermia was developed to buy time for resuscitative surgery and delayed resuscitation with cardiopulmonary bypass (CPB), but intact survival is limited by neuronal death associated with microglial proliferation and activation. Pharmacological modulation of microglia may improve outcome following CA. Systemic injection of liposome-encapsulated clodronate (LEC) depletes macrophages. To test the hypothesis that intrahippocampal injection of LEC would attenuate local microglial proliferation after CA in rats, we administered LEC or PBS into the right or left hippocampus, respectively. After rapid exsanguination and 6min no-flow, hypothermia was induced by ice-cold (IC) or room-temperature (RT) flush. Total duration of CA was 20min. Pre-treatment (IC, RTpre) and post-treatment (RTpost) groups were studied, along with shams (cannulation only) and CPB controls. On day 7, shams and CPB groups showed neither neuronal death nor microglial activation. In contrast, the number of microglia in hippocampus in each individual group (IC, RTpre, RTpost) was decreased with LEC vs. PBS by ∼34-46% (P<0.05). Microglial proliferation was attenuated in the IC vs. RT groups (P<0.05). Neuronal death did not differ between hemispheres or IC vs. RT groups. Thus, intrahippocampal injection of LEC attenuated microglial proliferation by ∼40%, but did not alter neuronal death. This suggests that microglia may not play a pivotal role in mediating neuronal death in prolonged hypothermic CA. This novel strategy provides us with a tool to study the specific effects of microglia in hypothermic CA.

Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial.

Objective:Emergency preservation and resuscitation (EPR) comprise a novel approach for resuscitation of exsanguination cardiac arrest victims. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass. Development of a rat EPR model would enable study of the molecular mechanisms of neuronal injury and the screening of novel agents for emergency preservation. Design:A prospective, randomized study. Setting:University research facility. Subjects:Adult male Sprague-Dawley rats. Interventions:Isoflurane-anesthetized rats were subjected to lethal hemorrhage (12.5 mL for 5 mins), followed by KCl-induced cardiac arrest and 1 min of no flow. Three groups (n = 6) were studied: hypothermic EPR (H-EPR; 0°C flush; target temperature, 15°C); normothermic EPR (N-EPR; 38°C flush); and controls. After 20 mins of H-EPR or N-EPR, resuscitation was initiated with cardiopulmonary bypass for 60 mins and mechanical ventilation. Controls were subjected to complete experimental preparation and anesthesia without cardiac arrest, followed by 60 mins of cardiopulmonary bypass and mechanical ventilation. Surviving rats were extubated 2 hrs later. Survival, Overall Performance Category (1, normal; 5, death), Neurologic Deficit Score, Histologic Damage Score, and biochemistry were assessed in survivors on day 7. Measurements and Main Results:All rats in H-EPR and control groups survived, whereas none of the rats in the N-EPR group had restoration of spontaneous circulation. All rats in the H-EPR and control groups achieved Overall Performance Category 1, normal Neurologic Damage Score, and normal or near normal Histologic Damage Score and biochemical markers of organ injury. Conclusions:We have established an EPR model in rats showing no neurologic injury, despite an exsanguination cardiac arrest, followed by 20 mins of EPR using miniaturized cardiopulmonary bypass. Establishment of this model should facilitate application of molecular tools to study the effects of hypothermic preservation and reperfusion and to screen novel pharmacologic adjuncts.

Deep hypothermia attenuates microglial proliferation independent of neuronal death after prolonged cardiac arrest in rats.

INTRODUCTION:Conventional resuscitation of exsanguination cardiac arrest (CA) victims is generally unsuccessful. Emergency preservation and resuscitation is a novel approach that uses an aortic flush to induce deep hypothermia during CA, followed by delayed resuscitation with cardiopulmonary bypass. Minocycline has been shown to be neuroprotective across a number of brain injury models via attenuating microglial activation. We hypothesized that deep hypothermia and minocycline would attenuate neuronal death and microglial activation and improve outcome after exsanguination CA in rats. METHODS:Using isoflurane anesthesia, rats were subjected to a lethal hemorrhagic shock. After 5 min of no flow, hypothermia was induced with an aortic flush. Three groups were studied: ice-cold (IC) flush, room-temperature (RT) flush, and RT flush followed by minocycline treatment (RT-M). After 20 min of CA, resuscitation was achieved via cardiopulmonary bypass. Survival, Overall Performance Category (1 = normal, 5 = death), Neurologic Deficit Score (0%–10% = normal, 100% = max deficit), neuronal death (Fluoro-Jade C), and microglial proliferation (Iba1 immunostaining) in hippocampus were assessed at 72 h. RESULTS:Rats in the IC group had lower tympanic temperature during CA versus other groups (IC, 20.9°C ± 1.3°C; RT, 28.4°C ± 0.6°C; RT-M, 28.3°C ± 0.7°C; P < 0.001). Although survival was similar in all groups (RT, 6/9; IC, 6/7; RT-M, 6/11), neurological outcome was better in the IC group versus other groups (Overall Performance Category: IC, 1 ± 1; RT, 3 ± 1; RT-M, 2 ± 1; P < 0.05; Neurologic Deficit Score: IC, 8% ± 9%; RT, 55% ± 19%; RT-M, 27% ± 16%; P < 0.05). Histological damage assessed in survivors showed selective neuronal death in CA1 and dentate gyrus, similar in all groups (P = 0.15). In contrast, microglial proliferation was attenuated in the IC group versus all other groups (P < 0.01). CONCLUSIONS:Deeper levels of hypothermia induced by the IC versus RT flush resulted in better neurological outcome in survivors. Surprisingly, deep hypothermia attenuated microglial activation but not hippocampal neuronal death. Minocycline had modest benefit on neurologic outcome in survivors but did not attenuate microglial activation in brain. Our findings suggest a novel effect of deep hypothermia on microglial proliferation during exsanguination CA.

Wearing the Wrong Size Latex Surgical Gloves Impairs Manual Dexterity

Universal precautions mandate that health care workers wear gloves when dealing with patients, often in situations requiring a high level of technical skill. Although it seems obvious that wearing the wrong size gloves could impair or prolong tasks involving manual dexterity, the issue has not been formally studied. We tested the hypothesis that wearing the wrong size gloves impairs manual dexterity. We administered a grooved pegboard test to 20 healthy, paid, volunteer health care workers. The subjects performed the test with bare hands and while wearing their preferred size of latex surgical gloves, gloves that were a full size smaller, and gloves that were a full size larger. Each subject did three runs with each size glove and three runs with bare hands. The time necessary to insert pegs was measured with a stopwatch. Peg insertion time was not affected by wearing preferred size gloves (vs. bare-handed) but was increased 7–10% by gloves that were either too small or too large (both effects: P < 0.05 vs. preferred size; both P < 0.001 vs. bare-handed). The subjects reported that the too-small gloves limited hand motion or hurt their hands, whereas the too-large gloves were clumsy but comfortable. Health care workers should wear gloves that fit properly when doing tasks that require manual dexterity. If the preferred size is unavailable, wearing gloves that are too large seems the best alternative.