Roland C. E. Francis

Inhaled Nitric Oxide Reduces Endothelial Activation and Parasite Accumulation in the Brain, and Enhances Survival in Experimental Cerebral Malaria

The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFNγ and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice. Inhaled nitric oxide administered in combination with artesunate, starting as late as 5.5 days post-infection, improved survival over treatment with artesunate alone (70% survival in the artesunate only vs. 100% survival in the artesunate plus iNO group, p = 0.03). These data support the clinical investigation of inhaled nitric oxide as a novel adjunctive therapy in patients with severe malaria.

Protective and Detrimental Effects of Sodium Sulfide and Hydrogen Sulfide in Murine Ventilator-induced Lung Injury.

Background: The antiinflammatory effects of hydrogen sulfide (H2S) and sodium sulfide (Na2S) treatment may prevent acute lung injury induced by high tidal volume (HVT) ventilation. However, lung protection may be limited by direct pulmonary toxicity associated with H2S inhalation. Therefore, the authors tested whether the inhalation of H2S or intravascular Na2S treatment can protect against ventilator-induced lung injury in mice. Methods: Anesthetized mice continuously inhaled 0, 1, 5, or 60 ppm H2S or received a single bolus infusion of Na2S (0.55 mg/kg) or vehicle and were then subjected to HVT (40 ml/kg) ventilation lasting 4 h (n = 4–8 per group). Results: HVT ventilation increased the concentrations of protein and interleukin-6 in bronchoalveolar lavage fluid, contributing to reduced respiratory compliance and impaired arterial oxygenation, and caused death from lung injury and pulmonary edema. Inhalation of 1 or 5 ppm H2S during HVT ventilation did not alter lung injury, but inhalation of 60 ppm H2S accelerated the development of ventilator-induced lung injury and enhanced the pulmonary expression of the chemoattractant CXCL-2 and the leukocyte adhesion molecules CD11b and L-selectin. In contrast, pretreatment with Na2S attenuated the expression of CXCL-2 and CD11b during HVT ventilation and reduced pulmonary edema. Moreover, Na2S enhanced the pulmonary expression of Nrf2-dependent antioxidant genes (NQO1, GPX2, and GST-A4) and prevented oxidative stress-induced depletion of glutathione in lung tissue. Conclusions: The data suggest that systemic intravascular treatment with Na2S represents a novel therapeutic strategy to prevent both ventilator-induced lung injury and pulmonary glutathione depletion by activating Nrf2-dependent antioxidant gene transcription.

Administration of hydrogen sulfide via extracorporeal membrane lung ventilation in sheep with partial cardiopulmonary bypass perfusion: a proof of concept study on metabolic and vasomotor effects

IntroductionAlthough inhalation of 80 parts per million (ppm) of hydrogen sulfide (H2S) reduces metabolism in mice, doses higher than 200 ppm of H2S were required to depress metabolism in rats. We therefore hypothesized that higher concentrations of H2S are required to reduce metabolism in larger mammals and humans. To avoid the potential pulmonary toxicity of H2S inhalation at high concentrations, we investigated whether administering H2S via ventilation of an extracorporeal membrane lung (ECML) would provide means to manipulate the metabolic rate in sheep.MethodsA partial venoarterial cardiopulmonary bypass was established in anesthetized, ventilated (fraction of inspired oxygen = 0.5) sheep. The ECML was alternately ventilated with air or air containing 100, 200, or 300 ppm H2S for intervals of 1 hour. Metabolic rate was estimated on the basis of total CO2 production (V˙CO2) and O2 consumption (V˙O2). Continuous hemodynamic monitoring was performed via indwelling femoral and pulmonary artery catheters.ResultsV˙CO2, V˙O2, and cardiac output ranged within normal physiological limits when the ECML was ventilated with air and did not change after administration of up to 300 ppm H2S. Administration of 100, 200 and 300 ppm H2S increased pulmonary vascular resistance by 46, 52 and 141 dyn·s/cm5, respectively (all P ≤ 0.05 for air vs. 100, 200 and 300 ppm H2S, respectively), and mean pulmonary artery pressure by 4 mmHg (P ≤ 0.05), 3 mmHg (n.s.) and 11 mmHg (P ≤ 0.05), respectively, without changing pulmonary capillary wedge pressure or cardiac output. Exposure to 300 ppm H2S decreased systemic vascular resistance from 1,561 ± 553 to 870 ± 138 dyn·s/cm5 (P ≤ 0.05) and mean arterial pressure from 121 ± 15 mmHg to 66 ± 11 mmHg (P ≤ 0.05). In addition, exposure to 300 ppm H2S impaired arterial oxygenation (PaO2 114 ± 36 mmHg with air vs. 83 ± 23 mmHg with H2S; P ≤ 0.05).ConclusionsAdministration of up to 300 ppm H2S via ventilation of an extracorporeal membrane lung does not reduce V˙CO2 and V˙O2, but causes dose-dependent pulmonary vasoconstriction and systemic vasodilation. These results suggest that administration of high concentrations of H2S in venoarterial cardiopulmonary bypass circulation does not reduce metabolism in anesthetized sheep but confers systemic and pulmonary vasomotor effects.

Nitric oxide synthase 3 contributes to ventilator-induced lung injury

Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HV(T); 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HV(T) ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HV(T) ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HV(T) ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide.

Quality management and benchmarking in emergency medicine.

Purpose of review Being critical in terms of time and complexity, emergency medicine is exposed to an emerging imperative for quality improvement strategies. We review current concepts and recent advances in the management of quality in emergency medicine. Recent findings There is a strong interdependence between quality of emergency healthcare provision and the education of emergency healthcare providers. Introduction of emergency medical residencies and highly qualified triage liaison physicians helps prevent the overcrowding of emergency departments, accelerate access to emergency medical care and improve patient satisfaction. New advances in detecting and reducing patient management errors include the collection of healthcare provider complaints and the classification of unpreventable and preventable deaths of patients within 1 week of admission via the emergency department. Medical record review and video recording have revealed that frequent patient management problems relate to shortcomings in the diagnostic process, clinical tasks, patient factors, and poor teamwork. Communication skills and patient data/documentation systems may effectively resolve these problems. Summary According to the available evidence, more performance improvement strategies need to be tested to delineate which process changes would be most effective in improving patient outcome in emergency medicine.

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Background: Nitrite (NO2 −) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. Methods: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n = 10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n = 14); groups 3–5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 &mgr;mol/kg IV; n = 6–8); group 6: HVT + NaNO2 + nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n = 6); group 7: HVT + NaNO2 + nitric oxide synthase inhibitor N&ohgr;-nitro-L-arginine methyl ester (n = 7); and group 8: HVT + NaNO2 + xanthine oxidoreductase inhibitor allopurinol (n = 6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. Results: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 &mgr;mol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. Conclusions: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.

Hydroxyethyl starch 130 kd/0.4 and albumin improve CVVH biocompatibility whereas gelatin and hydroxyethyl starch 200 kd/0.5 lead to adverse side effects of CVVH in anesthetized pigs.

Both fluid management and renal replacement therapies play a fundamental role in the treatment of critically ill patients. In a recent in vitro study, we have shown specific interactions of different colloids and the hemocompatibility of hemofilters. The present study was performed to compare the five most common fluids for volume resuscitation, i.e., normal saline (SAL), hydroxyethyl starch 130 kd/0.4 (HES130), hydroxyethyl starch 200 kd/0.5 (HES200), albumin (ALB), and gelatin (GEL) with respect to their interaction with continuous venovenous hemofiltration (CVVH) in anesthetized domestic pigs. Methods Animals (n = 63) were allocated randomly to the fluid type and the respective subgroups, which were divided into control and CVVH groups (n = 6 ndash; 7 per group). Bolus infusion of group specific fluid was followed by a bolus of heparin and the initiation of hemofiltration in CVVH groups. Thereafter, fluids were infused at constant rates, and heparin application was adjusted to keep the activated clotting time at 200 to 250 s. Hemodynamics, airway pressures, pulmonary gas exchange, diuresis, creatinine clearance, and blood cell counts were investigated during the entire procedure (10 ndash; 12 hours). Results Basics of in vivo effects of SAL, HES130, and ALB were not altered during CVVH. HES130 and ALB enabled stable hemocompatibility, diuresis, and hemodynamics in the respective groups. In contrast, organ functions were significantly different between control and CVVH groups when animals were treated with GEL or HES200. In particular, during CVVH, HES200 led to reduced platelet counts, deteriorated hemodynamics, and increasing airway pressures during CVVH. GEL led to increasing airway pressures, a decrease in pulmonary gas exchange, deteriorated hemodynamics, altered renal histomorphology, reduced platelet counts, and reduced hemoglobin. Conclusions Direct in vivo effects of colloids in anaesthetized and ventilated pigs are not predictable for their effects during CVVH. Interaction between CVVH and every volume substitute occur in a highly specific manner. This observation could be helpful to explain contradictory study results and should be considered for future study designs.

The haemodynamic and catecholamine response to xenon/remifentanil anaesthesia in Beagle dogs

The noble gas xenon seems to have minimal cardiovascular side-effects and so may be an ideal anaesthetic agent when investigating cardiovascular physiology. In comparison with standard modern anaesthetics, we investigated the haemodynamic and hormonal effects of xenon in Beagle dogs. After a 30 min baseline period, anaesthesia was induced with propofol and maintained with either (1) 1.2% isoflurane/70% nitrous oxide (N2O), (2) 0.8% isoflurane/0.5 µg/kg/min remifentanil or (3) 63% xenon/0.5 µg/kg/min remifentanil (n = 6 per group). Haemodynamics were recorded and blood samples taken before and 60 min after induction. Mean arterial blood pressure (MAP) was higher in conscious dogs than during isoflurane/N2O (86 ± 2 vs. 65 ± 2 mmHg, mean ± SEM) and isoflurane/remifentanil anaesthesia (95 ± 2 vs. 67 ± 3 mmHg), whereas MAP did not decrease significantly in response to xenon/remifentanil anaesthesia (96 ± 4 vs. 85 ± 6 mmHg). Bradycardia was present during isoflurane/remifentanil (54 ± 2/min) and xenon/remifentanil (40 ± 3/min), but not during isoflurane/N2O anaesthesia (98 ± 3/min, P < 0.05). Xenon/remifentanil anaesthesia induced the highest reduction in cardiac output (CO) (–61%), and the highest increase in systemic vascular resistance (+120%) among all treatment groups (P < 0.05). A simultaneous increase in endogenous adrenaline and noradrenaline concentrations could only be observed in the xenon/remifentanil group, whereas angiotensin II and vasopressin concentrations increased in all groups. In conclusion, xenon/remifentanil anaesthesia maintains MAP but reduces heart rate and CO and is associated with a considerable stimulation of vasopressor hormones in Beagle dogs. Therefore, xenon/remifentanil exerts a new quality of adverse haemodynamic effects different from volatile anaesthetics and may not perform better during studies of cardiovascular physiology.

Standard operating procedures as a tool to improve medical documentation in preclinical emergency medicine

Aim To evaluate the effect of standard operating procedures (SOPs) to improve the completion of patient care documentation items on patient care reports (PCRs) in a physician-staffed, 4500-calls-per-year preclinical ground emergency medical service (EMS) base. Methods Two series of PCRs were analysed before (n=505) and after (n=520) the introduction of SOPs. PCR forms were analysed for the rate of completion of documentation comparing prompted data in check boxes and non-prompted data written in blank spaces at the discretion of the emergency physician. The χ2 test for independence was used to assess the effect of SOPs and prompting on data completion rate. Results SOPs improved the documentation rate of numerous prompted and non-prompted items, independent of whether these items had a high (eg, Glasgow Coma Score: 91.5% vs 95.7%) or a low documentation rate during the pre-SOP period (eg, allergies: 6.2% vs 18.7%). Prompted items were more frequently documented than non-prompted items, both before and after the introduction of SOPs. Lowest rates were found among non-prompted items (eg, ‘last meal’ 3.6%). Conclusions In this EMS base, developing SOPs is an effective tool to improve the quality of PCRs and the rate of completion of documentation items. Check boxes on PCR forms seem to have an important impact as they prompt the initial assessment, treatment and documentation of the actions taken during an EMS call. Consequently, SOPs and check boxes may serve to improve the transition of important information to emergency department staff, and thus contribute to improved patient care.

Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs.

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg · kg(-1) · h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg · kg(-1) · h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg · kg(-1) · h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn · s · cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn · s · cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn · s · cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.