Ervant V. Nishanian

Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression through p38 MAPK activation

Nitric oxide (NO·) contributes to vascular collapse in septic shock and regulates inflammation. Here, we demonstrate in lipopolysaccharide (LPS)‐stimulated human THP‐1 cells and monocytes that NO· regulates interleukin (IL)‐8 and tumor necrosis factor α (TNF‐α) by distinct mechanisms. Dibutyryl‐cyclic guanosine 5′‐monophosphate (cGMP) failed to simulate NO·‐induced increases in TNF‐α or IL‐8 production. In contrast, dibutyryl‐cyclic adenosine monophosphate blocked NO·‐induced production of TNF‐α (P=0.009) but not IL‐8. NO· increased IL‐8 (5.7‐fold at 4 h; P=0.04) and TNF‐α mRNA levels (2.2‐fold at 4 h; P=0.037). However, nuclear run‐on assays demonstrated that IL‐8 transcription was slightly decreased by NO· (P=0.08), and TNF‐α was increased (P=0.012). Likewise, NO· had no effect on IL‐8 promoter activity (P=0.84) as measured by reporter gene assay. In THP‐1 cells and human primary monocytes treated with actinomycin D, NO· had no effect on TNF‐α mRNA stability (P>0.3 for both cell types) but significantly stabilized IL‐8 mRNA (P=0.001 for both cell types). Because of its role in mRNA stabilization, the p38 mitogen‐activated protein kinase (MAPK) pathway was examined and found to be activated by NO· in LPS‐treated THP‐1 cells and human monocytes. Further, SB202190, a p38 MAPK inhibitor, was shown to block NO·‐induced stabilization of IL‐8 mRNA (P<0.02 for both cell types). Thus, NO· regulates IL‐8 but not TNF‐α post‐transcriptionally. IL‐8 mRNA stabilization by NO· is independent of cGMP and at least partially dependent on p38 MAPK activation.

Cerebral blood flow affects dose requirements of intracarotid propofol for electrocerebral silence.

Background:The authors hypothesized that cerebral blood flow (CBF) changes will affect the dose of intracarotid propofol required to produce electrocerebral silence. Methods:The authors tested their hypothesis on New Zealand White rabbits. The first group of 9 animals received intracarotid propofol during (1) normoventilation, (2) hyperventilation, and (3) hypoventilation. The second group of 14 animals received intracarotid propofol with or without concurrent intraarterial verapamil, a potent cerebral vasodilator. The third group of 8 animals received bolus injection of propofol during normotension, during severe cerebral hypoperfusion, and after hemodynamic recovery. Results:In the first group, there was a linear correlation between the dose of intracarotid propofol and percent change (%&Dgr;) in CBF from the baseline due to changes in the minute ventilation, Total Dose (y) = 0.17 + 0.012 * %&Dgr; CBF (x), n = 27, r = 0.76. In the second group, the dose of propofol was also a function of CBF change after verapamil, Total Dose (y) = 0.98 + 0.1 * %&Dgr; CBF (x), n = 14, r = 0.75. In the third group, the duration of electrocerebral silence after intracarotid propofol (3 mg) was significantly increased with concurrent cerebral hypoperfusion compared with prehypoperfusion and posthypoperfusion values (141 ± 38 vs. 19 ± 24 and 16 ± 12 s, respectively, P < 0.0001). Conclusions:The authors conclude that CBF affects the dose requirements of intracarotid propofol required to produce electrocerebral silence. Furthermore, the manipulation of CBF might be a useful tool to enhance the efficacy of intracarotid drugs.

Carbon Dioxide Embolism During Hip Arthography in an Infant

A 6.1-kg, 4-mo-old girl (ASA physical status I) with possible bilateral congenital hip dislocations was scheduled for hip arthrography. She had no history of allergies and no cardiorespiratory abnormalities. Anesthesia was induced with halothane. The trachea was intubated after 2.7 mg of rocuronium and maintained with N,O/O, and 1% halothane. Mechanical ventilation was adjusted to ETco, levels of 3035 mm Hg. Her postinduction blood pressure was llO/ 56 mm Hg, heart rate was 130 bpm, and oxygen saturation (SpoJ was 100%. Twenty-gauge needles were inserted by the surgeons into each hip joint. Radiography showed that the tip of the needles were adjacent to the capital epiphysis on each side. Thirty milliliters of CO, was injected by a syringe into each hip joint. On fluoroscopy, it was noted that some of the CO, was tracked along the iliopsoas sheath. Attempts to remove the CO, were made. Blood was aspirated from one of the joint spaces. A total of 3 mL of diatrizoate was injected but partially escaped around the joint space. During the procedure, a sudden onset of oxygen desaturation to 80% was detected, which resolved spontaneously within 30 s. Approximately 3 min later, another episode of oxygen desaturation occurred (Spo, 40%). N,O was discontinued. The breathing circuit, the endotracheal tube, and the IV were checked. The breath sounds were equal on auscultation. On precordial auscultation, a millwheel murmur was detected, similar to “crunching of cornflakes.” ETco, was approximately 3 mm Hg. A progressive decrease in blood pressure and pulse rate were noted. Atropine 0.1 mg and ephedrine 5 mg were given. Surgery was stopped. Manual hyperventilation with 100% 0, and placement of the child in the head-down (Trendelenburg) position eliminated the harsh

Comparison of intracarotid anesthetics for EEG silence.

The goal of this study was to compare systemic and cerebrovascular effects of three anesthetic drugs (etomidate, thiopental, and propofol) when delivered by intracarotid and intravenous routes in doses that produce electrocerebral silence (electroencephalography [EEG]). EEG activity, mean arterial pressure (MAP), and laser Doppler flow as a proxy of cerebral blood flow (CBF) of 24 anesthetized New Zealand white rabbits were continuously recorded. Data were compared at three timepoints: baseline, during EEG silence, and after recovery of EEG activity. Drugs were randomly injected via the carotid artery to produce 10 minutes of EEG silence. After 30 minutes of rest, intravenous boluses of the same drug were injected to achieve 10 minutes of EEG silence. During EEG silence, transient hypotension was seen with intracarotid propofol, but there was no decrease in CBF. MAP and CBF did not decrease with either intracarotid etomidate or thiopental during EEG silence. Intracarotid/intravenous dose ratio of propofol (26%±22%; n=8, P<0.02) was much higher than that of etomidate and thiopental (14%±2% and 19%±11%, respectively; NS). Collectively, these results suggest intracarotid etomidate and thiopental are more useful than propofol in producing EEG silence because they offer better dose advantage and are less likely to impair cerebral or systemic hemodynamics.