Phillip S. Mushlin

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

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1 The present study evaluated the time‐dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C‐13 hydroxy metabolite, doxorubicinol. 2 Following addition of doxorubicin (175 μm) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 μm) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 μm), however, failed to produce time‐related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration‐response experiments with doxorubicinol (0.9–7.2 μm) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin‐treated than in doxorubicinol‐treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 μm doxorubicinol promoted a 15 fold greater release rate than 3 μm doxorubicin. 8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+ loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time‐dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Daunorubicin Cardiotoxicity EVIDENCE FOR THE IMPORTANCE OF THE QUINONE MOIETY IN A FREE-RADICAL-INDEPENDENT MECHANISM

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98+/-6% at 1 Hz, and 73+/-8 and 67+/-8% for 30 and 60 sec PRP, respectively, and 73+/-3 and 63 +/-3% at 2 and 3 Hz, respectively, for 88 microM Daun (P<0.05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force-frequency relationship or PRP contractions. Additional studies in Ca(2+)-loaded SR microsomes indicated that both Daun and 5-ID opened Ca(2+) release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca(2+) release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.

Negative pressure induced airway and pulmonary injury

PurposeTo describe negative pressure injury occurring during the use of a laryngeal mask airway (LMA) in which airway bleeding rather than pulmonary oedema was the major complication.Clinical FeaturesA patient presented to the day surgery unit for resection of a ganglion cyst on her right wrist. She underwent general anaesthesia using an LMA. and experienced severe laryngospasm and transient hypoxaemia (oxygen saturation to 66%) seven minutes after incision. This resolved within 90 sec of succinylcholine administration. Nonetheless, the LMA was removed, a tracheal tube was inserted atraumatically and positive pressure ventilation was maintained until the time of emergence, when fresh blood appeared in the tracheal tube. The blood ultimately became frothy, resembling pulmonary oedema fluid. Haemoptysis, continued postoperatively and led to the hospitalization of this ambulatory patient.ConclusionRapid development of large subatmosphenc pressures, as can occur dunng severe laryngospasm, may disrupt the tracheobronchial vasculature causing airway bleeding. This bleeding should be distinguished from negative pressure pulmonary oedema.RésuméObjectifRapporter une lésion causée par la pression négative survenue pendant l’utilisation d’un masque laryngé (ML). La présence de sang au niveau des voies respiratoires provenait d’une hémorragie et non d’un oedème pulmonaire.Éléments cliniquesUne patiente se présente à l’unité de chirurgie ambulatoire pour la résection d’un kyste au poignet droit. Pendant l’anesthésie générale au masque laryngé, il survient un laryngospasme grave avec hypoxie transitoire (saturation en oxygène à 66%) sept minutes après l’incision. La situation se rétablit à moins de 90 secondes après l’adminsitration de succinylcholine. On retire le ML et on introduit de façon atraumatique une canule endotrachéale. La ventilation mécanique est maintenue jusqu’au réveil alors que du sang frais apparaît dans la canule orotrachéale. Le sang devient plus tard spumeux comme dans le cas d’un oedème pulmonaire. C’est l’hémoptysie continue qui nécessite en postopératoire l’hospitalisation de cette patiente ambulante.ConclusionDe grandes pressions sous-atmosphériques soudaines, comme au moment d’un laryngospasme important, peuvent traumatiser la trame vasculaire trachéobronchique et provoquer ainsi un saignement des voies aériennes. II faut distinguer ce saignement de l’oedème pulmonaire par pression négative.

Transcutaneous PCO2 monitoring during laparoscopic cholecystectomy in pregnancy

PurposeRespiratory acidosis during carbon dioxide (CO2) insufflation has been suggested as a cause of spontaneous abortion and preterm labour following laparoscopic cholecystectomy during pregnancy. Capnography may not be adequate as a guide to adjust pulmonary ventilation during laparoscopic surgery and hence arterial carbon dioxide (PaCO2) monitoring has been recommended. We report the feasibility and benefits of transcutaneous carbon dioxide monitoring (PtcCO2) as an approach to optimise ventilation during laparoscopic surgery in pregnancy.MethodA healthy parturient received general anaesthesia for laparoscopic cholecystectomy. Pulmonary ventilation was adjusted to maintain end-tidal carbon dioxide (conventional PETCO2) at 32 mmHg during CO2 insufflation. A PtcCO2 monitor was used to trend PaCO2 throughout the procedure. Mechanical ventilation was interrupted every five minutes to obtain an end-tidal PCO2 value at large tidal volume (squeeze PETCO2).ResultsThe PtcCO2 increased from 39 mmHg before induction to 45 mmHg after CO2 insufflation. This corresponds to an estimated maximum PaCO2 of 39–40 mmHg during insufflation. The PtcCO2 gradually returned to pre-induction baseline values one hour after the termination of CO3 insufflation. Squeeze PETCO2 values approximated PtcCO2 more closely than did conventional PETCO2 values (P < 0.01).ConclusionContinuous PtcCO2 measurements as well as squeeze PetCO2 may be of clinical value in trending and preventing hypercarbia during laparoscopic surgery.RésuméObjectifL’acidose respiratoire durant l’insufflation au CO2 a été proposée comme cause d’avortement spontané et de travail prématuré à la suite de cholécystectomie laparoscopique durant la grossesse. La capnométrie peut ne pas être un guide adéquat pour ajuster la ventilation durant la chirurgie laparoscopique et de ce fait le monitoring du CO2 artériel a été recommandé. Cette étude rapporte la faisabilité et les bénéfices du monitorage du CO2 par voie transcutanée (PtcCO2) comme mesure d’optimalisation de la ventilation durant la chirurgie laparoscopique pendant la grossesse.MéthodeUne parturiente en bonne santé a subi une cholécystectomie par laparoscopie sous anesthésie générale. La PCO2 en fin d’expiration (PETCO2 conventionnelle) a été maintenue à 32 mmHg durant l’insufflation de CO2 en ajustant la ventilation pulmonaire. Un moniteur de PCO2 transcutanée a été utilisé pour établir la tendance durant la procédure. A toutes les cinq minutes, la ventilation mécanique était interrompue pour mesurer la PCO2 de fin d’expiration suite à un volume courant élevé (“Squeeze” PETCO2).RésultatsLa PtcCO2 était de 39 mmHg avant l’induction et a augmenté à 45 mmHg après l’insufflation avec le CO2. Ceci correspond à une PaCO2 maximale estimée de 39–40 mmHg durant l’insufflation. La PtcCO2 a retrouvé progressivement les valeurs de base une heure après la fin de l’insufflation de CO2. La PETCO2 suite à un volume courant élevé a une meilleure corrélation avec la PtcCO2 que la PETCO2 normale (P < 0,01 ).ConclusionLes mesures de la PtcCO2 de même que celles de la PETCO2 suite à un volume courant élevé peuvent être cliniquement utiles durant la chirurgie laparoscopique pour établir la tendance et prévenir l’hypercarbie.

Labour pain management in a parturient with an implanted intrathecal pump

PurposeWe report the peripartum anaesthetic management for vaginal delivery of a chronic pain patient with an implanted intrathecal pump. This is the first report describing labour analgesia in a patient with such a device. As intrathecal systems become more popular for the management of nonmalignant pain, this situation is likely to be encountered with increasing frequency in the future.Clinical featuresThe patient was a nulliparous 23-yr-old with a history of chronic hereditary pancreatitis whose intractable pain had been managed with intrathecal morphine 3 mg·day−1 via an implantable pump for four years. Inadequate time between presentation and onset of labour prevented us from using this system. Intravenous patient controlled analgesia with fentanyl using a bolus of 25 μg and a lockout of five minutes was ineffective and epidural analgesia using buprvacaine was initiated and resulted in satisfactory analgesia.ConclusionThe presence of an existing intrathecal delivery system does not preclude the use of supplemental epidural analgesia during labour.RésuméObjectifNous décrivons la prise en charge périgestationnelle de l’anesthésie d’une patiente porteuse d’une pompe sous-arachnoïdienne implantée. Il s’agit du premier compte rendu de l’analgésie en cours de travail d’une porteuse de ce dispositif. Comme le système de pompe sous-arachnoïdien est maintenant plus souvent utilisé pour la gestion de la douleur non cancéreuse, il est probable que cette situation se présentera plus fréquemment à l’avenir.Éléments cliniquesLa patiente. une nullipare de 23 ans, avait des antécédents de pancréatite chronique héréditaire et souffrait d’une douleur réfractaire contrôlée depuis quatre années par une pompe implantée. À cause du court délai entre l’admission et le début du travail, il était impossible de faire usage de ce système. L’analgésie intraveineuse contrôlée par la patiente au fentanyl avec un bolus de 25 μg et un intervalle de sécurité de cinq minutes étant inefficace, une analgésie épidurale à la bupivacaïne a été mise en marche et a été satisfaisante.ConclusionLa présence d’un système sous-arachnoïdien implanté pour l’analgésie n’est pas un obstacle à l’analgésie épidurale complémentaire pendant le travail.

Sedation, analgesia, and anesthesia for radiologic procedures.

Cardiovascular and interventional radiologic procedures often cause discomfort and anxiety. To promote patient acceptance of these procedures while facilitating radiologic evaluations, sedation, analgesia, or even anesthesia may be necessary. This review presents considerations in the management of sedation and analgesia before, during, and after the procedure. Potential adverse drug effects are discussed and emphasis is placed on patient monitoring during administration of medications. Our review points to a need for investigations of monitoring requirements and risk-benefit analysis of intravenous medication in radiologic practice. We encourage the establishment of working relationships between radiologists and anesthesiologists.

Aging alters the force-frequency relationship and toxicity of oxidative stress in rabbit heart

Adult (6 months) and senescent (greater than 5 years) rabbit atria were studied under conditions known to increase cytoplasmic calcium (increased frequency of contraction and oxidative stress). At a contraction frequency of 1/sec, cardiac relaxation (90% relaxation time) was similar in senescent and adult atria but at a frequency of 2 or 3/sec, relaxation was significantly slower in senescent preparations (P less than 0.05). Additional experiments indicated that H2O2 (500 microM), a powerful oxidant, increased resting force and decreased developed force (DF) much more rapidly in senescent than adult atria; the maximum decrease in DF, however, was less in senescent preparations (adult = 81 +/- 6% and senescent = 42 +/- 27% of pre-H2O2 values; P less than 0.05). Age-related differences in effects of H2O2 did not result simply from a decreased ability of senescent hearts to detoxify an oxidative stress by the glutathione pathway. Both basal glutathione (GSH) concentrations and the H2O2-mediated decreases in GSH were similar in adult and senescent ventricular preparations, as were activities of glutathione peroxidase and glutathione reductase. These observations suggest that interventions known to increase cytoplasmic calcium can amplify age-related impairments of cardiac relaxation through mechanisms that may be independent of the glutathione pathway.

Decreased sensitivity of neonatal rabbit sarcoplasmic reticulum to anthracycline cardiotoxicity

Anthracyclines are useful chemotherapeutic agents whose utility is limited by the development of irreversible cardiotoxicity. When tested, the pediatric population demonstrates an increased sensitivity to the cardiotoxicity of this class of agents, although the reasons for this increased sensitivity are unclear. The sarcoplasmic reticulum (SR) is a target for anthracycline cardiotoxicity in adults, but the effects of anthracycline on the SR in developing myocardium have not been examined. It may be possible to gain insight into the mechanisms of cardiotoxicity through a comparative approach. We compared the acute effects of doxorubicin, daunorubicin, and caffeine on contractile function in adult and neonatal rabbit myocardium. Frequency-dependent contratility, 90% relaxation times, and postrest potentiated contractions (a uniquely SR-dependent phenomenon) in adult myocardium were inhibited in a concentration-dependent manner. Neonatal myocardium, however, was resistant to the effects of these agents. The degree of contractile dysfunction wa consistent with the difference in SR maturation between adult and developing myocardium Anthracyclines exhibited effects similar to those of caffeine, an agent known to render the Sr nonfunctional by the depletion of the releasable SR calcium pool. These results suggest that anthracyclines induce acute cardiac lesions through effects on the SR in adults, whereas cardiotoxic effects in the developing myocardium may proceed by a different mechanism.

Beneficial effects of perfluorochemical artificial blood on cardiac function following coronary occlusion

This study compares the effects of perfluorochemical artificial blood versus whole blood on the systolic and diastolic function of regionally ischemic myocardial preparations. Regional ischemia was produced by ligation of the circumflex coronary artery in isolated, blood-perfused rabbit hearts. Three minutes after occlusion, half the hearts were switched from the blood perfusate to perfluorochemical artificial blood; the other half continued to be perfused with blood. Isovolumic left ventricular (LV) developed pressure, dP/dt and resting pressure were monitored before, and for 2 hours after coronary occlusion. After 90 minutes of regional ischemia, perfluorochemical-treated hearts exhibited significantly greater developed pressure than those perfused with blood (78 +/- 6% versus 61 +/- 5% of preligation values; P less than 0.05). At the end of the experiment, LV dP/dt was 21% greater in the perfluorochemical-perfused group than in the blood-perfused group (74 +/- 8% versus 53 +/- 10%; P less than 0.01). Perfluorochemical perfusion also preserved diastolic function by preventing the 58% increase in left ventricular chamber stiffness (i.e., resting pressure; P less than 0.01) associated with circumflex ligation. Thus, in the present model of regional ischemia, perfluorochemical artificial blood is significantly better than blood at maintaining both systolic and diastolic myocardial function after a major coronary artery has been occluded.