Sarcoplasmic reticulum calcium release is stimulated and inhibited by daunorubicin and daunorubicinol.

Cardiac effects of anthracyclines or their metabolites may include both the stimulation and inhibition of Ca(2+) release from sarcoplasmic reticulum. In this study, the ability of daunorubicin and its primary metabolite, daunorubicinol, to stimulate and inhibit Ca(2+) release from canine sarcoplasmic reticulum (SR) vesicles was investigated. It was observed that both daunorubicin and daunorubicinol were several fold more potent at inhibiting than they were at stimulating SR Ca(2+) release. Respective IC50 inhibition of daunorubicin and daunorubicinol for caffeine-induced calcium release was 1.2 and 0.6 microM, and for spontaneous Ca(2+) release was 3 and 1 microM. EC50's for daunorubicin- and daunorubicinol-induced calcium release were 30 and 15 microM, respectively. Inhibition of either spontaneous or caffeine-induced SR Ca(2+) release was inversely related to the amount of Ca(2+) loaded into the SR before exposure to daunorubicin or daunorubicinol. The free-radical scavenger dithiothreitol did not attenuate the ability of anthracyclines to inhibit SR Ca(2+) release. A nonquinone daunorubicin derivative, 5-iminodaunorubicin, was less potent than daunorubicin at inhibiting caffeine-induced Ca(2+) release. These data suggest anthracyclines and their metabolites may produce cardiotoxicity through free-radical independent, concentration-dependent effects on SR Ca(2+) release. These effects involve either inhibition or stimulation of SR Ca(2+) release and are partly dependent upon the presence of the quinone moiety.

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.

Transcutaneous PCO2 monitoring during laparoscopic cholecystectomy in pregnancy.

PURPOSE: Respiratory 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. METHOD: A 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). RESULTS: The 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 CO2 insufflation. Squeeze PETCO2 values approximated PtcCO2 more closely than did conventional PETCO2 values (P < 0.01). CONCLUSION: Continuous PtcCO2 measurements as well as squeeze PETCO2 may be of clinical value in trending and preventing hypercarbia during laparoscopic surgery.

Anaesthesia in Barbados.

PURPOSE: To describe the anaesthesia services in Barbados: to present the major challenges confronting the Anaesthesia Department of the government-owned Queen Elizabeth Hospital (QEH): and to describe the Department's approaches to optimise safety and cost-effectiveness of anaesthesia at QEH. SOURCE OF INFORMATION: Authors (KBS, HSLM, RAH), who collectively provided more than 50 yr of anaesthesia at QEH; the Dean (ERW) of the University of West Indies Medical School (Barbados campus); archives of Barbados; and records of QEH. PRINCIPAL FINDINGS: The government of Barbados provides modern health care services to all of its citizens, primarily at QEH. Barbados, however, has tight financial constraints, infrastructural limitations, and a bureaucratic administration that predispose QEH's Anaesthesia Department to unexpected depletions of drugs and disposable supplies, sporadic shortages of personnel and functioning equipment, and occasional quality assurance problems. To deal with such problems, the Anaesthesia Department has implemented several pro-active measures: establishing an audit system to prevent depletion of imported drugs and supplies: training local personnel to maintain equipment: purchasing an oxygen concentrator to reduce oxygen costs: decreasing nitrous oxide use (expensive in Barbados): and initiating its own quality and safety standards. CONCLUSION: Continuous delivery of high quality, cost-effective anaesthesia care requires thoughtful planning by administrators and judicious resource allocations. Health care administrators and clinical departments need to work together closely to establish a framework that enables departments to play a major role in determining how the institution's limited financial resources are best allocated to meet the departmental priorities.

Negative pressure induced airway and pulmonary injury.

PURPOSE: To 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 FEATURES: A 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. CONCLUSION: Rapid development of large subatmospheric pressures, as can occur during severe laryngospasm, may disrupt the tracheobronchial vasculature causing airway bleeding. This bleeding should be distinguished from negative pressure pulmonary oedema.

Labour pain management in a parturient with an implanted intrathecal pump.

PURPOSE: We 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 FEATURES: The 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 micrograms and a lockout of five minutes was ineffective and epidural analgesia using bupivacaine was initiated and resulted in satisfactory analgesia. CONCLUSION: The presence of an existing intrathecal delivery system does not preclude the use of supplemental epidural analgesia during labour.

Aging increases the cardiotoxicity of daunorubicin and daunorubicinol in the rat.

This study examined effects of aging on the cardiac response in vitro to daunorubicin, a cancer chemotherapeutic agent that causes cardiotoxicity. Left ventricular trabeculae carneae from adult (aged 6-9 months) and old (aged 24-28 months) Fischer 344 rats were placed in oxygenated, physiological buffer. Preparations were treated with daunorubicin (175 microM) or saline (controls) over a 210-minute study period. Daunorubicin-induced decline in contractility (DS and dS/dt) was greater in old compared to adult myocardium (p < .02). Similarly, cardiac relaxation (90% relaxation time) was more impaired by daunorubicin in older preparations (p < 01). Although daunorubicin concentrations were unaffected by age, daunorubicinol concentrations in ventricular strips increased with time to a greater extent in the older group (p < .05). This study suggests that senescence increases the acute in vitro cardiotoxicity of daunorubicin and that the metabolite, daunorubicinol, may contribute to this toxicity.

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 determining 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 microM) 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 microM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 microM), 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 microM) 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 microM doxorubicinol promoted a 15 fold greater release rate than 3 microM 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-induced cardiac injury in the rabbit: a role for daunorubicinol?

This study evaluated potential contributions of daunorubicin and its principle metabolite, daunorubicinol, to the cardiotoxicity of daunorubicin therapy. Daunorubicin (15 mg/kg) or placebo (normal saline) was administered by iv bolus to New Zealand white rabbits and 3 to 4 days later, hearts were removed to measure contractility (dF/dt), concentrations of daunorubicin and daunorubicinol, and evidence of oxidative stress on glutathione and glutathione peroxidase. Contractile function of isolated atria and papillary muscles was depressed (p < 0.05). Daunorubicinol exceeded daunorubicin concentration in the heart (p < 0.005) with a ratio of metabolite to parent drug of 26 in atrial and 32 in ventricular tissue. There was a significant correlation between peak plasma (r = -0.63; p < 0.05) or cardiac concentration (r = -0.78; p < 0.02) of daunorubicinol, but not daunorubicin, and depression of dF/dt in papillary muscles. In separate in vitro studies, daunorubicinol at a concentration (5.5 micrograms/g tissue or 10 microM) approximating that observed ex vivo in heart inhibited Ca2+ uptake into cardiac sarcoplasmic reticulum vesicles by 39 +/- 3%, whereas 10 microM daunorubicin (14-fold higher than actual ex vivo cardiac concentrations) did not demonstrate any detectable inhibition. Daunorubicin treatment failed to significantly alter concentrations of GSH or GSSG or activities of glutathione peroxidase in the heart. Thus, cardiac dysfunction observed 3 to 4 days after a single dose of daunorubicin did not clearly relate to oxidative stress, but was associated with a cardiac concentration of daunorubicinol that appeared sufficiently high to impair Ca2+ metabolism.

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.

Doxorubicin cardiotoxicity: analysis of prevailing hypotheses.

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.

Reversal of bupivacaine epidural anesthesia by intermittent epidural injections of crystalloid solutions.

This study was designed to determine whether epidural motor blockade could be reversed by postoperative injections of crystalloid solutions via the epidural catheter. Twenty-seven patients (ASA physical status I, nonlaboring) had epidural anesthesia with 0.75% bupivacaine for elective cesarean delivery. Postoperatively, patients were randomized to receive three 15-mL injections (over 30 min) of crystalloid solutions (normal saline or Ringer's lactate) or no treatment (control) via the epidural catheter. Degree of motor and sensory blockade was evaluated with an investigator blinded to treatment group. Rate of resolution of sensory blockade was not different among groups. However, time for resolution of motor blockade was more than twice as long in the control group than in either treatment group (control = 178 +/- 70 min vs Ringer's lactate = 84 +/- 44 min, normal saline = 70 +/- 38 min, P = 0.001). The data suggest that unwanted motor blockade due to epidural anesthesia can be reversed by epidural injections of crystalloid solutions.

Effects of oral caffeine on postdural puncture headache. A double-blind, placebo-controlled trial.

Forty postpartum patients with postdural puncture headache (PDPH) were randomly assigned to receive oral caffeine (300 mg) or a placebo. Intensity of headache, quantitated using a visual analogue pain scale (VAS), was assessed immediately before drug administration and 4 and 24 h later. Relief of PDPH measured as delta VAS (initial VAS - VAS at 4 h) was significantly better in the caffeine than in the placebo group (P = 0.014). Six patients (30%) whose PDPH was relieved by caffeine at 4 h had recurrence of symptoms the following day. Our study demonstrates that caffeine administered orally provides relief, albeit if sometimes transient, from PDPH with minimal side effects.