Knut Arvid Kirkebøen

Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines

Nitric oxide (NO) and prostaglandines (PGs) are important in regulation of vascular tone and blood flow. Their contribution in human cutaneous circulation is still uncertain. We inhibited NO synthesis by infusing N(G)-monomethyl-L-arginine (L-NMMA) in the brachial artery (16 micromol/min for 5 min) and reversed it by intraarterial infusion of L-arginine (40 micromol/min for 7.5 min). PG synthesis was inhibited by the cyclooxygenase inhibitor aspirin (600 mg over 5 min intravenously). Basal cutaneous perfusion and perfusion responses during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were recorded by laser Doppler flowmetry (LDF). We performed wavelet transforms of the measured signals. Mean spectral amplitude within the frequency interval from 0.0095 to 1.6 Hz and mean and normalized amplitudes of five intervals around 1, 0.3, 0.1, 0.04, and 0.01 Hz were analysed. The oscillations with frequencies around 1, 0.3, 0.1, and 0.04 Hz are influenced by the heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, and the neurogenic activity of the vessel wall, respectively. We have previously shown that the oscillation with a frequency around 0.01 Hz is modulated by the vascular endothelium. L-NMMA reduced mean value of the LDF signal by approximately 20% (P = 0.0067). This reduction was reversed by L-arginine. Mean value of the LDF signals during ACh and SNP iontophoresis did not change after infusion of L-NMMA. Aspirin did not affect mean value of the LDF signal or the LDF signal during ACh or SNP iontophoresis. Before interventions the only significant difference between the effects of ACh and SNP was observed in the frequency around 0.01 Hz, where ACh increased normalized amplitude to a greater extent than SNP. L-NMMA abolished this difference, whereas it reappeared after infusion of L-arginine (P = 0.0084). Aspirin did not affect this difference (P = 0.006). We conclude that basal cutaneous blood flow and the endothelial dependency of the oscillation around 0.01 Hz are partly mediated by NO, but not by endogenous PGs. Other aspects of human cutaneous circulation studied are not regulated by NO or PGs.

Poor agreement between respiratory variations in pulse oximetry photoplethysmographic waveform amplitude and pulse pressure in intensive care unit patients.

Background: To identify fluid responsiveness, a correlation between respiratory variations in pulse pressure (&Dgr;PP) and respiratory variations in pulse oximetry photoplethysmographic waveform amplitude (&Dgr;POP) in mechanically ventilated patients has been demonstrated. To evaluate the agreement between the two methods, knowledge about the repeatability of the methods is imperative. However, no such data exist. Based on knowledge of slow oscillation in skin blood flow, the authors hypothesized that the variability of &Dgr;POP would be larger than that of &Dgr;PP when calculations were performed continuously over a long recording period. Methods: Respiration, continuous invasive blood pressure, pulse oximetry, and skin microcirculation were recorded in 14 mechanically ventilated intensive care unit patients. No intravenous fluid challenges were given, and no other interventions were performed during the measurements. Seventy consecutive comparisons between &Dgr;PP and &Dgr;POP were calculated for each of the 14 patients. Results: For all patients, &Dgr;POP was 13.7 ± 5.8% and &Dgr;PP was 5.8 ± 2.6% (P < 0.001). There was a larger intraindividual (8.94 vs. 1.29; P < 0.001) and interindividual (26.01 vs. 5.57; P < 0.001) variance of &Dgr;POP than of &Dgr;PP. In six patients, there was no significant correlation between &Dgr;PP and &Dgr;POP. A Bland–Altman plot showed poor agreement between the two methods. Conclusion: A large variability of &Dgr;POP and a poor agreement between &Dgr;PP and &Dgr;POP limits &Dgr;POP as a tool for evaluation of fluid responsiveness in intensive care unit patients. This is in contrast to &Dgr;PP, which shows a small variability.

Nitric oxide indices in human septic shock

ObjectivesTo study the relation between nitrite, nitrate, nitrotyrosine, and nitrosothiols as NO indices in human septic shock. DesignA prospective clinical study. SettingIntensive care units in a university hospital and a central county hospital. PatientsSixteen patients admitted for septic shock. Nine healthy volunteers served as controls. InterventionsNone. Measurements and Main ResultsPatients with septic shock had a hyperdynamic circulatory response and required infusion of at least two vasopressors to maintain systemic blood pressure. Four episodes of recurrent shock occurred in two patients. Heparinized plasma was collected once daily for analysis of NO indices. Peak plasma concentrations of nitrite + nitrate (NOx) were elevated in first episodes of septic shock; 144 ± 39 &mgr;M vs. controls, 20 ± 3 &mgr;M (p < .05). Peak plasma NOx concentrations in recurrent shocks were; 160 ± 19 &mgr;M. Peak plasma concentrations of 3-nitrotyrosine (NT) were elevated in primary septic shock 102 ± 19 pmol·mL−1 vs. controls 14 ± 6 pmol·mL−1 (p < .05). Peak NT concentrations were 117 ± 37 pmol·mL−1 in recurrent septic shock. Peak plasma NT concentrations did not coincide with peak NOx concentrations in half of the episodes of septic shock. Plasma NT was elevated (59 ± 15 pmol·mL−1 vs. controls 14 ± 6 pmol·mL−1, p < .05) in patients with normal plasma NOx concentrations throughout septic shock. Plasma concentrations of nitrosothiols did not change during septic shock. ConclusionsPlasma concentrations of NOx and NT are elevated in primary episodes of septic shock and may also be elevated in secondary septic shock, but too few episodes of recurrent septic shock occurred to allow firm conclusions. Plasma concentrations of NT are elevated in patients with septic shock with normal plasma NOx concentrations, indicating that plasma concentrations of NOx may not always accurately reflect NO production. Reactive nitrogen species may be formed in septic shock, and measuring both NOx and NT may give a better indication of NO production in septic shock than NOx alone. Plasma levels of nitrosothiols did not change during septic shock.

The Effects of General Anesthesia on Human Skin Microcirculation Evaluated by Wavelet Transform

BACKGROUND:Time-frequency analysis of the laser Doppler flowmetry signal, using wavelet transform, shows periodic oscillations at five characteristic frequencies related to the heart (0.6–2 Hz), respiration (0.15–0.6 Hz), myogenic activity in the vessel wall (0.052–0.15 Hz), sympathetic activity (0.021–0.052 Hz), and very slow oscillations (0.0095–0.021), which can be modulated by the endothelium-dependent vasodilator acetylcholine. We hypothesized that wavelet transform of laser Doppler flowmetry signals could detect changes in the microcirculation induced by general anesthesia, such as alterations in vasomotion and sympathetic activity. METHODS:Eleven patients undergoing faciomaxillary surgery were included. Skin microcirculation was measured on the lower forearm with laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside before and during general anesthesia with propofol, fentanyl, and midazolam. The laser Doppler flowmetry signals were analyzed using wavelet transform. RESULTS:There were significant reductions in spectral amplitudes in the 0.0095–0.021 (P < 0.01), the 0.021–0.052 (P < 0.001), and the 0.052–0.15 Hz frequency interval (P < 0.01) and a significant increase in the 0.15–0.6 Hz frequency interval. General anesthesia had no effect on the difference between acetylcholine and sodium nitroprusside on relative amplitudes in the 0.0095–0.021 Hz frequency interval (P < 0.001). CONCLUSION:General anesthesia reduces the oscillatory components of the perfusion signal related to sympathetic, myogenic activity and the component modulated by the endothelium. However, the iontophoretic data did not reveal a specific effect on the endothelium. The increase in the 0.15–0.6 Hz interval is related to the effect of mechanical ventilation.

Preconditioning - endogenous defence mechanisms of the heart.

The term ‘preconditioning’ refers to the paradoxical phenomenon that pretreatment with a potential noxious stress‐stimulus can increase cellular tolerance to subsequent noxious stress‐stimuli. This was first described in an experimental model in dogs in which short‐lasting periods of myocardial ischemia resulted in reduced infarction during a subsequent long‐lasting coronary artery occlusion. Similar observations have also been made in other species and in other organs. During the last few years, the term preconditioning has been expanded to include pretreatment with other physical stress‐stimuli or pharmacological agents that can increase cellular resistance to injury. The phenomenon probably represents a general adaptive response to cellular stress, but mechanisms involved are not fully clarified.

Human skin microcirculation after brachial plexus block evaluated by wavelet transform of the laser Doppler flowmetry signal.

Background:The skin microcirculation may be evaluated noninvasively by laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside. Wavelet transform of the perfusion signal shows periodic oscillations of five characteristic frequencies in the interval 0.0095–1.6 Hz. The aim of the current study was to investigate alterations in skin microcirculation induced by brachial plexus block, with emphasis on the periodic oscillations. Methods:Healthy nonsmokers undergoing hand surgery (n = 13) were anesthetized with brachial plexus block, using bupivacaine, lidocaine, and epinephrine. Skin microcirculation was evaluated by laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside before and after brachial plexus block. Wavelet transform of the perfusion signal was performed. As a control group, 10 healthy nonsmokers were included. Results:In the anesthetized arm, skin perfusion after brachial plexus block increased from 19 (12–30) to 24 (14–39) arbitrary units (P < 0.01). A significant increase was also seen in the contralateral arm from 17 (14–32) to 20 (14–42) arbitrary units (P < 0.01). After brachial plexus block, spectral analysis revealed a significant reduction in relative amplitude of the oscillatory components within the 0.0095- to 0.021- (P < 0.001) and 0.021- to 0.052-Hz (P < 0.001) intervals in the anesthetized arm. Conclusion:Alterations in skin microcirculation induced by brachial plexus block can be evaluated by wavelet transform of the laser Doppler flowmetry signal. Brachial plexus block reduces the oscillatory components within the 0.0095- to 0.021- and 0.021- to 0.052-Hz intervals of the perfusion signal. These alterations are related to inhibition of sympathetic activity and a possible impairment of endothelial function.

Enhanced endothelium-dependent vasodilatation in human skin vasculature induced by physical conditioning

Functional alterations to the endothelial cells of the vascular system may contribute to the improved circulatory performance induced by physical conditioning. We evaluated microvascular reactivity to iontophoretic application of acetylcholine (ACh) and sodium nitroprusside (SNP) through the skin and blood perfusion measurements in the same area using laser Doppler flowmetry. Whereas ACh acts on smooth muscle cells of the vascular system via the production of vasodilator substances from the endothelium, SNP is an endothelium-independent vasodilator acting on vascular smooth muscle cells directly. The study was performed using two groups of subjects with different levels of aerobic endurance, long distance runners competing at national level (n = 9) and controls (n = 9). The subjects were tested for 40 min on a treadmill before and after an exercise test at 80% of their maximal oxygen uptake. During stimulation by ACh cutaneous perfusion increased to a higher level in the athletes than in the controls (overall P < 0.05), whereas an acute period of exercise abolished this difference (overall P > 0.6). There was no significant difference between the athletes and the controls with respect to the SNP-induced increase in cutaneous perfusion either before (P > 0.9) or after (P > 0.9) exercise. The higher cutaneous perfusion responses to stimulation with ACh in the athletes than in the controls may support the hypothesis that regular exercise modifies the responsiveness of the cutaneous endothelium. The difference in ACh-induced perfusion and in unstimulated forearm perfusion between the two groups was present only at rest. This finding indicated that mechanisms were introduced during exercise, which compensated for the lower endothelial sensitivity to stimulation in the controls at rest.

Microembolization in pigs: effects on coronary blood flow and myocardial ischemic tolerance.

Coronary microembolization has been reported to increase coronary blood flow (CBF) through adenosine release. Because adenosine may increase ischemic tolerance against infarction, we tested the hypothesis that myocardial microembolization, a common finding in patients with ischemic heart disease, induces cardioprotection. Additionally, because the use of microspheres is a common tool to measure tissue perfusion, the effects of small amounts of microspheres on CBF were examined. Using anesthetized pigs, we measured CBF with a transit time flow probe on the left anterior descending coronary artery (LAD). In six pigs the relationship between the amount of injected microspheres (0-40 × 106, 15 μm in diameter, left atrial injections) and the effect on CBF was examined. Coronary hyperemia occurred, which was linearly related to the amount of microspheres injected: maximal increase in CBF (%) = 2.8 ± 1.5 (SE) + (5.8 ± 0.7 × 10-7 × number of injected microspheres). Because injection of 40 × 106 microspheres induced a long-lasting hyperemic response, which could be blocked by 8- p-sulfophenyl theophylline, ischemic tolerance was examined in five other pigs after two injections, each of 40 × 106microspheres, at a 30-min interval. Six control pigs had no injections. Ischemic tolerance was evaluated by measuring infarct size (tetrazolium stain) as the percentage of area at risk (fluorescent particles) after 45 min of LAD occlusion followed by 2 h of reperfusion. Pretreatment by microspheres increased infarct size from 60 ± 3% of area at risk in control animals to 84 ± 6% ( P< 0.05). The injection of microspheres induced a significant hyperemic flow response without causing necrosis by itself. We conclude that microembolization, evoking coronary hyperemia, does not improve but reduces myocardial ischemic tolerance against infarction in pigs.Coronary microembolization has been reported to increase coronary blood flow (CBF) through adenosine release. Because adenosine may increase ischemic tolerance against infarction, we tested the hypothesis that myocardial microembolization, a common finding in patients with ischemic heart disease, induces cardioprotection. Additionally, because the use of microspheres is a common tool to measure tissue perfusion, the effects of small amounts of microspheres on CBF were examined. Using anesthetized pigs, we measured CBF with a transit time flow probe on the left anterior descending coronary artery (LAD). In six pigs the relationship between the amount of injected microspheres (0-40 x 10(6), 15 micrometer in diameter, left atrial injections) and the effect on CBF was examined. Coronary hyperemia occurred, which was linearly related to the amount of microspheres injected: maximal increase in CBF (%) = 2.8 +/- 1.5 (SE) + (5.8 +/- 0.7 x 10(-7) x number of injected microspheres). Because injection of 40 x 10(6) microspheres induced a long-lasting hyperemic response, which could be blocked by 8-p-sulfophenyl theophylline, ischemic tolerance was examined in five other pigs after two injections, each of 40 x 10(6) microspheres, at a 30-min interval. Six control pigs had no injections. Ischemic tolerance was evaluated by measuring infarct size (tetrazolium stain) as the percentage of area at risk (fluorescent particles) after 45 min of LAD occlusion followed by 2 h of reperfusion. Pretreatment by microspheres increased infarct size from 60 +/- 3% of area at risk in control animals to 84 +/- 6% (P < 0.05). The injection of microspheres induced a significant hyperemic flow response without causing necrosis by itself. We conclude that microembolization, evoking coronary hyperemia, does not improve but reduces myocardial ischemic tolerance against infarction in pigs.

Dynamic variables of fluid responsiveness during pneumoperitoneum and laparoscopic surgery

Few data exist on dynamic variables predicting fluid responsiveness during laparoscopic surgery. The aim of this study was to explore the effects of laparoscopy on four dynamic variables: respiratory variations in pulse pressure (ΔPP), stroke volume variation by Vigileo/FloTrac (SVV Vigileo), pleth variability index (PVI) and respiratory variations in pulse oximetry plethysmography waveform amplitude (ΔPOP), and their relation to fluid challenges during laparoscopic surgery.

The anesthesia in abdominal aortic surgery (ABSENT) study: a prospective, randomized, controlled trial comparing troponin T release with fentanyl-sevoflurane and propofol-remifentanil anesthesia in major vascular surgery.

Background:On the basis of data indicating that volatile anesthetics induce cardioprotection in cardiac surgery, current guidelines recommend volatile anesthetics for maintenance of general anesthesia during noncardiac surgery in hemodynamic stable patients at risk for perioperative myocardial ischemia. The aim of the current study was to compare increased troponin T (TnT) values in patients receiving sevoflurane-based anesthesia or total intravenous anesthesia in elective abdominal aortic surgery. Methods:A prospective, randomized, open, parallel-group trial comparing sevoflurane-based anesthesia (group S) and total intravenous anesthesia (group T) with regard to cardioprotection in 193 patients scheduled for elective abdominal aortic surgery. Increased TnT level on the first postoperative day was the primary endpoint. Secondary endpoints were postoperative complications, nonfatal coronary events and mortality. Results:On the first postoperative day increased TnT values (>13 ng/l) were found in 43 (44%) patients in group S versus 41 (43%) in group T (P = 0.999), with no significant differences in TnT levels between the groups at any time point. Although underpowered, the authors found no differences in postoperative complications, nonfatal coronary events or mortality between the groups. Conclusions:In elective abdominal aortic surgery sevoflurane-based anesthesia did not reduce myocardial injury, evaluated by TnT release, compared with total intravenous anesthesia. These data indicate that potential cardioprotective effects of volatile anesthetics found in cardiac surgery are less obvious in major vascular surgery.