Simon Gelman

Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury.

ISCHEMIA contributes to the pathophysiology of many conditions faced by anesthesiologists, including myocardial infarction, peripheral vascular insufficiency, stroke, and hypovolemic shock. Although restoration of blood flow to an ischemic organ is essential to prevent irreversible cellular injury, reperfusion per se may augment tissue injury in excess of that produced by ischemia alone. For example, the histologic changes of injury after 3 h of feline intestinal ischemia followed by 1 h of reperfusion are far worse than the changes observed after 4 h of ischemia alone. Cellular damage after reperfusion of previously viable ischemic tissues is defined as ischemia–reperfusion (I-R) injury. Ischemia–reperfusion associated with thrombolytic therapy, organ transplantation, coronary angioplasty, aortic cross-clamping, or cardiopulmonary bypass results in local and systemic inflammation. If severe enough, the inflammatory response after I-R may result in the systemic inflammatory response syndrome or multiple organ dysfunction syndrome (MODS), which account for 30–40% of the mortality in tertiary referral intensive care units. Thus, I-R injury may extend beyond the ischemic area at risk to include injury of remote, nonischemic organs.

Venous Function and Central Venous Pressure : A Physiologic Story

The veins contain approximately 70% of total blood volume and are 30 times more compliant than arteries; therefore, changes in blood volume within the veins are associated with relatively small changes in venous pressure. The terms venous capacity, compliance, and stressed and unstressed volumes are defined. Decreases in flow into a vein are associated with decreases in intravenous pressure and volume, and vice versa. Changes in resistance in the small arteries and arterioles may affect venous return in opposite directions; this is explained by a two-compartment model: compliant (mainly splanchnic veins) and noncompliant (nonsplanchnic veins). Effects of intrathoracic and intraabdominal pressures on venous return and central venous pressure as well as the value of central venous pressure as a diagnostic variable are discussed.

Regional blood flow during isoflurane and halothane anesthesia.

Cardiac output distribution and regional blood flow in 18 dogs during isoflurane and halothane anesthesia were studied in dose-related fashion. Surgical preparation consisted of left thoracotomy and placement of catheters in the left atrium and aorta through a femoral artery. Regional blood flow was studied one week after surgical preparation using a microsphere technique at the three stages: awake, 1 MAC, and 2 MAC of inhalation anesthesia. At each stage of the experiment, two sets of microspheres (15-and 9-μm diameter), labeled with different isotopes, were used simultaneously. Both anesthetics increased cerebral blood flow, decreased blood flow through preportal area, and preserved renal blood flow. Isoflurane increased hepatic artery blood flow at both levels of anesthesia, while halothane preserved the flow during 1 MAC and decreased it at 2 MAC. Apparently, isoflurane provided better oxygenation to the liver than halothane. Myocardial blood flow was increased during isoflurane (despite decrease in blood pressure and cardiac output) and decreased during halothane anesthesia. Isoflurane appears to be a coronary vasodilator with potential beneficial (improvement in myocardial blood supply) as well as hazardous (“steal effect”) effects on the heart.

Liver circulation and function during isoflurane and halothane anesthesia.

Hepatic arterial blood flow (HABF) and portal blood flow (PBF) were measured in 18 dogs while awake and during isoflurane and halothane anesthesia. Surgical preparation 1 week before the measurements consisted of a left thoracotomy, placement of a left atrial catheter, and insertion of another catheter into the distal aorta via the left femoral artery. Cardiac output and liver blood flow were determined using microspheres at three stages: stage 1—awake state; stage 2—after 45 min of 1 MAC of isoflurane (eight dogs) or halothane (10 dogs) anesthesia; and stage 3—after 45 min of 2 MAC of inhalation anesthesia. Half-life and fractional clearance for indocyanine green (ICG) were determined 1 day before the experiment (awake state), and at the end of stages 2 and 3. Mean arterial pressure (MAP) and cardiac index (CI), as well as PBF, decreased during isoflurane and halothane anesthesia. HABF increased significantly during isoflurane anesthesia, remained unchanged during 1 MAC of halothane anesthesia, and significantly decreased during 2 MAC of halothane anesthesia. Apparently, hepatic oxygen supply was maintained much better during isoflurane than during halothane anesthesia. PBF correlated with CI during halothane (r = 0.97) and, to a certain extent, with MAP during isoflurane (r = 0.66). HABF correlated with CI and MAP during halothane (r = 0.74 and 0.71, respectively) but did not correlate with systemic hemodynamic variables during isoflurane. ICG half-life significantly increased during 1 and 2 MAC of halothane anesthesia. The degree of increase did not correlate with the level of anesthesia or the decrease in total hepatic blood flow. Isoflurane anesthesia was not accompanied by significant changes in ICG half-life. The data suggest that halothane has a more deleterious effect on liver blood flow than does isoflurane and, in addition, interferes with liver cell ability to absorb and excrete ICG.

Hepatic circulation during surgical stress and anesthesia with halothane, isoflurane, or fentanyl.

Hepatic blood flow and the oxygen supply I uptake relation were studied in 19 miniature pigs using labeled microspheres. Changes in hepatic arterial blood flow and portal blood flow, as well as total hepatic blood flow during halothane anesthesia were more closely associated with changes in mean arterial pressure (MAP) and cardiac output than during anesthesia with isoflurane or fentanyl. Halothane or isoflurane administered in concentrations that decreased MAP by approximately 30% were accompanied by decreases in hepatic oxygen delivery (DO2th) averaging 46% during halothane and 31% during isoflurane anesthesia and parallel decreases in hepatic blood flow. In concentrations that decreased MAP by 50%, halothane and isoflurane decreased DO2th 61 and 37%, respectively. DO2th was maintained (statistically insignificant, 23% increase) during both doses of fentanyl administered (20 μg/kg followed by 0.17 μg-kg −1 min−1, and 50 μg/kg followed by 0.42 μg-kg −1-min−1). Hepatic oxygen uptake increased 50% during fentanyl and was maintained at baseline levels during both doses of halothane and isoflurane anesthesia. Oxygen content in hepatic venous blood was maintained at baseline levels during fentanyl and isoflurane administration and was decreased by both concentrations of halothane anesthesia. The hepatic oxygen supply demand ratio was maintained at baseline levels after both doses of fentanyl and during isoflurane administered in a concentration that decreased blood pressure 30%; the ratio decreased during isoflurane administered in a concentration decreasing blood pressure by 50% and during both doses of halothane anesthesia. The data suggest that during surgical stress, anesthesia, using fentanyl or isoflurane in a concentration decreasing blood pressure by ≤30%, provides adequate hepatic oxygen supply, whereas anesthesia with isoflurane in a concentration decreasing blood pressure >30%, or with halothane in any concentration studied, results in inadequate hepatic oxygen supply.

Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics

THIS article focuses on the effects of catecholamines on the splanchnic circulation that influence systemic hemodynamics (particularly venous return and cardiac output) under normal physiologic conditions. Because of its required brevity, this article could not address other important hemodynamic effects of catecholamines, such as those that result from metabolic alterations, effects on the circulatory system that do not involve the splanchnic organs, and those that accompany major pathophysiologic states, such as sepsis or congestive heart failure. Anatomy and Blood Supply

Anesthetics Impact the Resolution of Inflammation

Background Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation. Methods and Findings Using murine peritonitis induced by zymosan and a systems approach, we report that lidocaine delayed and blocked key events in resolution of inflammation. Lidocaine inhibited both PMN apoptosis and macrophage uptake of apoptotic PMN, events that contributed to impaired PMN removal from exudates and thereby delayed the onset of resolution of acute inflammation and return to homeostasis. Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B4, prostaglandin E2 and anti-inflammatory lipoxin A4, in the cell-free peritoneal lavages. Addition of a lipoxin A4 stable analog, partially rescued lidocaine-delayed resolution of inflammation. To identify protein components underlying lidocaines actions in resolution, systematic proteomics was carried out using nanospray-liquid chromatography-tandem mass spectrometry. Lidocaine selectively up-regulated pro-inflammatory proteins including S100A8/9 and CRAMP/LL-37, and down-regulated anti-inflammatory and some pro-resolution peptides and proteins including IL-4, IL-13, TGF-â and Galectin-1. In contrast, the volatile anesthetic isoflurane promoted resolution in this system, diminishing the amplitude of PMN infiltration and shortening the resolution interval (Ri) ∼50%. In addition, isoflurane down-regulated a panel of pro-inflammatory chemokines and cytokines, as well as proteins known to be active in cell migration and chemotaxis (i.e., CRAMP and cofilin-1). The distinct impact of lidocaine and isoflurane on selective molecules may underlie their opposite actions in resolution of inflammation, namely lidocaine delayed the onset of resoluion (Tmax), while isoflurane shortened resolution interval (Ri). Conclusions Taken together, both local and volatile anesthetics impact endogenous resolution program(s), altering specific resolution indices and selective cellular/molecular components in inflammation-resolution. Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

Midazolam Pharmacodynamics and Pharmacokinetics during Acute Hypovolemia

This study was designed to test the hypothesis that acute hypovolemia would compromise the compensatory hemodynamic mechanisms to midazolam and decrease its metabolic clearance. Experiments were performed on seven chronically instrumented female beagle dogs. Animals received a single intravenous dose of midazolam, 10 mg/kg, 4 days apart during normovolemic (N) and hypovolemic (H) states in a random sequence. Hypovolemia was achieved by the withdrawal of 26 ml/kg of blood, equivalent to one-third of the calculated blood volume. Midazolam plasma concentrations were determined at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 h after midazolam injection. Elimination half-life (t1/2 β) was significantly longer and total clearance was significantly lower during H than during N. Initial distribution half-life, central compartment volume, total volume of distribution, and plasma protein binding were similar in both N and H states. Midazolam caused a significant decrease in systolic blood pressure (SBP) and an increase in heart rate (HR) during N, and produced significant decreases in SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP) during H. Midazolam led to similar per cent decreases in blood pressure and cardiac output in states N and H; however, the absolute values of blood pressure and cardiac output were significantly (P < 0.001) lower in the hypovolemic state than in the normovolemic state. These data suggest that the hypotensive effects of midazolam, like those of other intravenous induction agents, could be potentiated by volume depletion.

Transcranial Doppler and rCBF compared in carotid endarterectomy.

In eight patients undergoing carotid endarterectomy, the mean velocity and an index of pulse amplitude in the middle cerebral artery were monitored continuously by transcranial doppler ultrasound. rCBF was measured by intracarotid injection of 133 Xenon shortly before and at the time of the carotid artery occlusion, and again a few minutes after carotid flow was reestablished. Comparison of the mean velocity in the MCA and the cortical convexity rCBF revealed relatively little hysteresis in their relationship from prior to after the occlusion. There was however, considerable variability in this relationship among patients. Both the rCBF and the velocity decreased substantially at occlusion in three cases, neither changed very much in three. While in two, though the rCBF decreased significantly, the velocity did not change. The index of pulse amplitude was somewhat more sensitive to the occlusion, decreasing in the seven cases in which it was recorded, including one in which the rCBF did not change.

Circulatory responses to laryngoscopy: the comparative effects of placebo, fentanyl and esmolol.

The circulatory response to a 30-second laryngoscopy followed by orotracheal intubation was recorded in 60 patients of ASA physical status III or TV undergoing a variety of non-cardiac surgical procedures. Patients were randomly allocated to either the placebo, esmolol (500μg·kg−1·min− 1 × 6 minutes, followed by 300 μg· kg− 1· min− 1 × 9 minutes), or fentanyl (0.8μg·kg− 1.min− 1 × 10 minutes) group, and the observer was blinded to the infusion administered. Esmolol blunted the heart rate (HR) response, while fentanyl decreased it below the baseline and maintained it there, in spite of laryngoscopy. Similarly, fentanyl decreased the systolic (SBP), mean (MBP) and diaslolic blood pressures (DBP) significantly below the baseline, while these pressures were either retained at or elevated slightly above control in the esmolol group. In these doses, the HR response to laryngoscopy was more effectively blocked by fentanyl, while esmolol better retained perfusion pressure. There were no complications or ischaemic electrocardiographic changes in any patient.RésuméNous avons mesuré la riponse hemodynamique à une laryngoscopie de 30 secondes suivie d’ une intubation orotrachéale chez 60 patients de classe ASA III ou IV devant subir diverses interventions chirurgicales autres que cardiaques. Le hasard determinant si la manoeuvre allait être précédée d’ un placebo, desmolol (500μg·kg− 1·min− 1 × 6 minutes, puis 300 μg·kg− 1· min− 1 × 9 minutes), ou de fentanyl (0.8 μg·kg− 1·min− 1× 10 minutes) et ce, à l’insu d’un observateur neutre. L’esmolol limitait l’accélération dupouls tandis que le fentanyl ralentissait le coeur avant, pendant et apris la laryngoscopie. Avec le fentanyl, on a vu s’abaisser significativement les pressions artérielles systoliques, moyennes et diastoliques alors qu’elles se maintenaient ou s’élevaient légèrement avec l’esmolol. Ainsi, aux doses employées, le fentanyl prévient mieux la réponse chronotrope à la laryngoscopie alors que l’esmolol maintient la pression de perfusion. Nous n’avons noté aucune complication ni aucun signe électrocardiographique d’ischémie pendant cette etude.