Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging.

RATIONALE AND OBJECTIVES: To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound. METHODS: The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection. RESULTS: The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. CONCLUSIONS: SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.

Effects of fenoldopam on systemic and splanchnic haemodynamics and oxygen delivery/consumption relationship during hyperdynamic ovine endotoxaemia.

OBJECTIVE: To evaluate the use of a selective dopamine-1 agonist (fenoldopam) to provide selective splanchnic vasodilatation during sustained hypotensive endotoxaemia in sheep. DESIGN: Randomised, controlled, experimental study. SETTING: Animal research laboratory. SUBJECTS: 12 adult instrumented, midazolam-sedated sheep. INTERVENTIONS: The animals were randomised to receive a 20-min continuous infusion of dopamine (10 microg x kg(-1) x min(-1), fenoldopam (10 microg x kg(-1) x min(-1) and noradrenaline (1 microg x kg(-1) x min(-1)) under control conditions and 12 h after endotoxaemia was induced by a continuous infusion of Escherichia coli endotoxin producing a stable hyperdynamic state simulating human septic shock. This drug dosage was selected to produce a 25-30% increase in cardiac output by all three drugs during control conditions. MEASUREMENTS AND RESULTS: Systemic and splanchnic haemodynamic data were continuously obtained and systemic and splanchnic oxygen delivery (DO2) and consumption (VO2) were calculated. Hyperdynamic hypotensive endotoxaemia did not modify the splanchnic and renal reduction in DO2 and the vasoconstrictive reactivity to noradrenaline observed during control conditions. In contrast, endotoxaemia abolished the fenoldopam and dopamine-induced increase in splanchnic DO2 (especially in the coeliac trunk) observed during control conditions. CONCLUSIONS: During sustained hyperdynamic endotoxaemia, the dopaminergic-induced selective increase in coeliac trunk blood flow is abolished, most probably because of an already maximally vasodilated splanchnic circulation which prevented dopamine or fenoldopam to vasodilate this area further. Contrary to common belief, selective dopamine-1 agonist administration under these conditions may therefore not be beneficial to the splanchnic organs, though it improves whole body DO2 and VO2.

Systemic and splanchnic oxygen supply-demand relationship with fenoldopam, dopamine and noradrenaline in sheep.

The effects of intravenous administration of fenoldopam (0.3-10 micrograms.kg-1.min-1), dopamine (1-10 micrograms.kg-1.min-1) and noradrenaline (0.1-1 micrograms.kg-1.min-1) on systemic and splanchnic haemodynamics and oxygen supply-demand relationship were studied in 12 chronically instrumented, sedated sheep. Fenoldopam produced dose-dependent peripheral and splanchnic vasodilatation without change in arterial blood pressure. The coeliac trunk and portal vein blood flows were particularly sensitive to fenoldopam, whereas dopamine vasodilated these vascular beds only at high doses. Renal blood flow was not influenced by dopamine or fenoldopam, but decreased by noradrenaline. Fenoldopam maintained systemic oxygen extraction constant by increasing both oxygen supply and demand, while noradrenaline and dopamine increased oxygen supply more than demand, thus decreasing oxygen extraction. Both dopamine and fenoldopam increased oxygen delivery to the splanchnic organs while noradrenaline reduced it. Splanchnic oxygen consumption decreased with noradrenaline and increased with dopamine, resulting in a conserved oxygen extraction with both drugs, whereas oxygen consumption remained constant at all doses of fenoldopam infusion (i.e. dose-dependent decreased oxygen extraction). Both noradrenaline and fenoldopam, but not dopamine, were accompanied by increased portal lactataemia. We conclude that in sheep fenoldopam is a potent and selective splanchnic vasodilator but without vasodilatator effect on the renal circulation. The portal lactataemia associated with a decreased splanchnic oxygen extraction may present a significant limitation for some clinical applications of this drug.

Time course of systemic and renal plasma prostanoid concentrations and renal function in ovine hyperdynamic sepsis.

1. We continuously recorded systemic and renal haemodynamic changes, and arterial, renal venous and urinary concentrations of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2, and determined their relationship to renal function in an ovine model of progressive hyperdynamic sepsis. 2. Nine chronically instrumented unanaesthetized sheep were given a continuous intravenous infusion of Escherichia coli endotoxin (20 ng min-1 kg-1) for 3 days. 3. Within the first 12 h of infusion, endotoxin induced a major hypotensive septic syndrome, including a persistent 30% reduction in mean arterial pressure, a 50% decrease in systemic vascular resistance and a 50% increase in mean pulmonary artery pressure, associated with severe lactacidaemia. 4. Renal blood flow decreased by 40%, and creatinine clearance, urine flow, and fractional sodium excretion decreased by more than 75%, of baseline values. After 12 h of endotoxin infusion, cardiac output increased two-fold and renal blood flow recovered to baseline values, whereas creatinine clearance remained depressed. Four sheep died between 13 and 22 h of endotoxaemia; these animals (allocated to group 1) presented a significantly and persistently more reduced renal blood flow (-23%) and creatinine clearance (-77%) after 4 h than the remaining five sheep (allocated to group 2), which survived more than 36 h (-16% and -21%, respectively), whereas systemic and pulmonary haemodynamic and gas exchange data remained similar in both groups. 5. The more pronounced decreases in renal blood flow, creatinine clearance and urine flow in group 1 were associated with higher plasma renin activity and plasma 6-keto-prostaglandin F1 alpha concentrations and a lower fractional urinary excretion of 6-keto-prostaglandin F1 alpha than in group 2, whereas plasma thromboxane B2 concentrations were similarly increased in both groups. Plasma prostaglandin E2 concentrations and urinary excretion were not notably affected by endotoxin infusion in either group. 6. Our results are not in favour of a significant renal production of any of these three prostanoids during endotoxaemia. In both groups, values of creatinine clearance were linearly correlated with simultaneous mean arterial pressure values after starting endotoxin infusion (group 1: creatinine clearance = 1.99 x mean arterial pressure--105, r = 0.95; group 2: creatinine clearance = 2.06 x mean arterial pressure--104, r = 0.80).(ABSTRACT TRUNCATED AT 400 WORDS)

Intrathecal midazolam reduces isoflurane MAC and increases the apnoeic threshold in rats.

The purpose of this study was to examine the anaesthetic requirement of intrathecal midazolam in a dose-response fashion in isoflurane-anaesthetized, tracheostomized rats, and to evaluate the apnoeic threshold after each intrathecal midazolam dose. Intrathecal midazolam, 5, 10, 20, and 30 micrograms, was administered to 25 anaesthetized tracheotomized rats. Isoflurane MAC was determined by the tail-clamp method. The effect of intrathecal midazolam on the apnoeic threshold was evaluated, and light and electron microscopy studies were performed on cervical, thoracic and lumbar sections of the spinal cord to investigate possible midazolam-induced neurotoxic effects. Intrathecal midazolam 5, 10, 20 and 30 micrograms decreased isoflurane MAC by 16%, 31%, 42%, and 53% respectively (P < 0.05). The apnoeic threshold was increased by midazolam 5 micrograms (from a PaCO2 of 4.25 +/- 0.55 to 5.28 +/- 0.76 kPa, P < 0.05) when compared with baseline values, but not further by additional doses. Light and electron microscopy studies on sections taken from the spinal cord of four animals did not show any morphological changes suggestive of midazolam-induced neurotoxicity when compared with similar preparations obtained from controls. These data suggest that intrathecal midazolam possesses dose-dependent antinociceptive properties which, associated with the ceiling effect of the apnoeic threshold obtained at the lowest midazolam dose and the lack of neurotoxic effects, may potentiate inhalational anaesthesia without producing marked respiratory depression.

Sequential changes in the splanchnic circulation during continuous endotoxin infusion in sedated sheep: evidence for a selective increase of hepatic artery blood flow and loss of the hepatic arterial buffer response.

On-line recording of the sequential changes in systemic, pulmonary, mesenteric, hepatic and renal circulations during onset of endotoxaemia and at 24 h of established hyperdynamic sepsis were evaluated in seven chronically instrumented and sedated sheep receiving a continuous intravenous infusion of Escherichia coli endotoxin (20 ng min-1 kg-1). A transient and significant (P < 0.05) pulmonary arterial vaso-constriction was noted after 13 +/- 4 min, and was followed immediately by a simultaneous significant decrease of coeliac trunk, superior mesenteric artery, and portal vein blood flow to below 50% of baseline values. The superior mesenteric artery and portal vein blood flows partially recovered pre-endotoxin levels to 69 and 75% of baseline, respectively, after 70 min of endotoxin infusion. In contrast, the coeliac trunk blood flow remained reduced for a more prolonged period of time, but then completely recovered baseline values at 100 min. The response of the hepatic artery was biphasic, and consisted of a transient (5-10 min) vasoconstriction at 40 min followed by transitory increase of hepatic artery blood flow reaching a maximum of 921% of baseline values at 102 min. Contrasting with the early changes observed in mesenteric vascular resistances mostly unrelated to systemic haemodynamics, the response of the renal vasculature appeared to be more dependent on changes of renal perfusion pressure. A follow-up at 24 h revealed that the continuous intravenous infusion of endotoxin reproduced some of the most characteristic features of human sepsis with increased cardiac output and decreased vascular resistances of all vascular beds. We conclude that hepatic artery blood flow is selectively and considerably increased in early endotoxaemia in sheep independently of changes in portal vein blood flow, suggesting a disregulation of the physiologic hepatic arterial buffer response, most probably secondary to an increased liver oxygen demand required for phagocytosis, transport, and digestion of the the sudden overload of bacterial endotoxins.

Evaluation of sufentanil anesthesia obtained by a computer-controlled infusion for cardiac surgery.

To determine the "therapeutic window" for sufentanil in cardiac surgery, nine hemodynamically stable, lightly premedicated patients were anesthetized with sufentanil to undergo coronary artery bypass grafting. Sufentanil was administered by a computer-controlled infusion pump programmed with an infusion scheme based on average sufentanil pharmacokinetics. The presence of somatic or hemodynamic responses to tracheal intubation, skin incision, sternotomy, and during electrocauterization, to isolate the internal mammary artery were correlated with plasma concentrations of sufentanil. The concentration versus response/no response relationships were analyzed by application of the logistic (Hill) equation. The CP50 of sufentanil to suppress responses to intubation, incision, and sternotomy was 7.1 ng/mL and for mediastinal dissection it was 12.7 ng/mL. Interpatient variability was as much as that reported previously for other opioids in other types of surgical patients. The computer-controlled infusion scheme consistently produced sufentanil plasma concentrations in excess of the target concentrations, but there was a strong correlation between target and actual sufentanil concentrations (r = 0.88, P < 0.05).

Epidural morphine reduces halothane MAC in humans.

The effect of epidural morphine sulphate (4 mg in 10 ml saline) on the minimum alveolar concentration of halothane was investigated in a double-blind, randomized fashion in ten adult patients undergoing abdominal surgery, and compared with the minimum alveolar concentration of halothane after epidural administration of 10 ml saline in a similar group of patients. Morphine sulphate, administered through the epidural catheter 98 +/- 33 min before to skin incision reduced the minimum alveolar concentration of halothane by 28% (0.57% vs 0.78%, P < 0.05).

Sequential changes in renal oxygen consumption and sodium transport during hyperdynamic sepsis in sheep.

The sequence of changes in systemic and renal oxygen delivery (QO2) and consumption (VO2) and renal function in an ovine model of progressive hyperdynamic sepsis was investigated. Nine chronically instrumented awake sheep were given a continuous intravenous Escherichia coli endotoxin infusion (20 ng.kg-1.min-1) for 3 days. After 8 h of the infusion, systemic arterial blood pressure and vascular resistance stayed decreased by 30% (P less than 0.001). Systemic QO2 progressively increased to a maximum of 157% of baseline values at 24 h and was associated with a decreased O2 extraction ratio from 33 +/- 2 (SE) to 23 +/- 2% (P less than 0.05), resulting in an unchanged systemic VO2. Renal blood flow and renal QO2 decreased by 40% during the first 12 h, returning to and staying at baseline values after 24 h. Renal VO2 decreased significantly by 35% at 12 h and then partially recovered to baseline values. Plasma creatinine clearance was maximally reduced to 25% of baseline values at 12 h and thereafter remained significantly (P less than 0.01) below 50% of baseline values. Both total and fractional sodium excretion fell at 12 h by 95 and 74%, respectively, and remained reduced over time, indicating conserved tubular function. The ratio of moles of sodium reabsorbed to moles of O2 consumed by the kidney was transiently reduced, from 33.4 +/- 4.1 to 12.4 +/- 3.6 at 12 h (P less than 0.05), indicating a relative increase in energy expenditure for tubular transport or renal synthetic activities, but recovered to baseline values after 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventricular fibrillation following local application of cocaine and epinephrine for nasal surgery.

We report the case of a 17-year-old female patient, scheduled for septoplasty under general anesthesia, who developed ventricular fibrillation after intranasal application of cocaine (350 mg) and submucosal injection of lidocaine (20 mg) with epinephrine (100 micrograms). Resuscitation by external chest compression was successful, and normal sinus rhythm was reestablished after lidocaine injection (50 mg, i.v.). The cardiac risk of the combined administration of cocaine and epinephrine during general anesthesia are discussed.

[Major surgery of the thoracic wall: preoperative preparation, peri-and postoperative care]. / Chirurgie majeure de la paroi thoracique: préparation préopératoire, traitement péri- et postopératoire.

Major chest wall surgery causes significant changes in respiratory function during the peri- and postoperative phases. These are predominantly due to lateral position, use of a double lumen endotracheal tube, one-lung anesthesia, loss of functional intrathoracic volume, postoperative pain and local hypoventilation, pulmonary superinfection and right heart dysfunction. In the present short review pathophysiological mechanisms, appropriate monitoring techniques and some therapeutic modalities are discussed.

Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs.

The anesthetic interactions of midazolam and fentanyl were determined in terms of enflurane MAC reduction in dogs. In part 1, 8 animals received an intravenous (iv) loading dose of fentanyl followed by a constant infusion at 0.05 micrograms.kg-1.min-1 to produce a stable enflurane MAC reduction of approximately 20%. Midazolam was then administered in a series of three incremental loading doses and infusions (2.4, 9.6, and 28.8 micrograms.kg-1.min-1 previously determined to produce enflurane MAC reductions of approximately 30, 45, and 60%, respectively. Enflurane MAC was determined for each infusion. Then fentanyl was discontinued; naloxone 1 mg/kg was administered; and enflurane MAC was determined. In part 2, six dogs received a loading dose and a continuous infusion of fentanyl (0.2 micrograms.kg-1.min-1) designed to produce a stable enflurane MAC reduction of approximately 40%. A series of two incremental loading doses and infusions of midazolam (2.4 and 28.8 micrograms.kg-1.min-1) were added, and MAC determinations were repeated at each infusion rate. Then midazolam was discontinued; flumazenil (RO 15-1788) 1.5 mg/kg was administered; and enflurane MAC was determined. The fentanyl concentrations in plasma remained stable at 1.0 +/- 0.3 ng/ml (mean +/- standard deviation [SD], part 1) and 3.1 +/- 0.5 ng/ml (part 2) throughout the study and, in the absence of midazolam, reduced enflurane MAC by 28 +/- 11 and 44 +/- 5%, respectively. The addition of midazolam produced significant further reductions in enflurane MAC, but the reductions were less than those predicted on the basis of an additive interaction. Naloxone returned enflurane MAC reduction to that expected for midazolam alone (part 1).(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane.

The plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC50: MAC--the end-tidal concentration at which half the dogs moved in response to clamping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group 1, four dogs in Group 2 received ketamine as a continuous infusion of 300 micrograms.kg-1.min-1 for 5 hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 micrograms/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2 beta = 122 +/- 9 vs. 141 +/- 40 min (mean +/- SD) and CL = 18.1 +/- 5.9 vs. 13.9 +/- 2.5 ml.kg-1.min-1, respectively. When administered as a continuous infusion (Group 2), KET remained relatively stable at 22.1 +/- 4.6 micrograms/ml for 5 hr. The degree of MAC reduction remained relatively stable at 73% during the continuous infusion. Finally, the enflurane MAC reduction vs. KET was established over a wide range of plasma concentrations in 4 additional dogs (Group 3). This study determined that the pharmacokinetics of ketamine were consistent under two different experimental conditions and demonstrated the relationship between plasma concentration and anesthetic effect in the dog.

Assessing the adequacy of fentanyl anesthesia: plasma concentrations and lower esophageal contractility.

Assessing the adequacy of anesthesia in the paralyzed patient is usually based on sympathetic and hemodynamic responses to noxious stimulation. Absence of such responses does not guarantee adequate anesthesia. A device monitoring the amplitude of provoked lower esophageal, contractility (PLEC) and the rate of spontaneous lower esophageal contractility (SLEC) has been developed as a potential monitor of the adequacy of anesthesia. This study determined the reliability of this device for monitoring anesthetic depth in 20 patients receiving fentanyl infusions who were undergoing coronary artery surgery and who were hemodynamically stable in the preoperative period. Premedication included midazolam 0.05 mg/kg i.m. and ranitidine 2 mg/kg p.o. Anesthesia was induced with fentanyl 50 micrograms/kg administered over 10 min and maintained by a fentanyl infusion 0.2 micrograms.kg-1.min-1. Following endotracheal intubation, a disposable esophageal monitoring probe, equipped with provoking and measuring balloons, was inserted and both the amplitude of provoked (PLEC) and the rate of spontaneous lower esophageal contractions (SLEC) were displayed and recorded. Precisely defined clinical signs of inadequate anesthesia included both somatic and hemodynamic responses to noxious stimulations. The presence of these responses was correlated with PLEC and SLEC and with fentanyl concentrations in plasma at specific times of noxious stimulation during the period preceding initiation of cardiopulmonary bypass. A total of 208 episodes of noxious stimulation were recorded at insertion of the nasal temperature probe (n = 8), at penetration of the skin by towel clips (n = 25), at skin incision (n = 20), at sternotomy (n = 20) and during multiple episodes of electrocauterization (n = 135). These provoked 52 clinical responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung function during anesthesia and respiratory insufficiency in the postoperative period: physiological and clinical implications.

This review covers the physiological and clinical implications of lung function during anesthesia and respiratory insufficiency in the postoperative period. We have divided it into 3 main sections: 1) lung function changes induced by anesthesia and surgery, in which the impact on pulmonary mechanics, ventilation/perfusion changes and gas exchange are examined; 2) physiological implications of postoperative respiratory function secondary to decreased alveolar ventilation, development of atelectasis, and interstitial lung edema; and 3) clinical implications of postoperative respiratory failure. In this last section we analyze the current therapeutic modalities available to reduce the incidence of postoperative respiratory failure, as well as related morbidity and mortality.

Evaluation of patients at risk for protamine reactions.

Patients with neutral protamine Hagedorn and protamine-zinc insulin-dependent diabetes, a history of fish allergy, or prior vasectomy have been reported to be at an increased risk for protamine reactions after cardiopulmonary bypass because of prior sensitization. We prospectively evaluated cardiac surgical patients with prior vasectomies and fish allergies and retrospectively evaluated a cohort of 3245 consecutive cardiac surgical patients requiring cardiopulmonary bypass over a 2-year period for protamine-containing insulin use and clinical evidence of adverse reactions after protamine administration for heparin reversal after cardiopulmonary bypass. Clinical reactions to protamine did not occur in six patients with fish allergies or 16 patients with prior vasectomies. There was one reaction (0.6%) in 160 patients with neutral protamine Hagedorn insulin-dependent diabetes. The incidence of clinical reactions in the other patients was 2/3085 (0.06%). The incidence of clinical reactions in the patients with neutral protamine Hagedorn insulin-dependent diabetes is not significantly different from that in other patients. We conclude that prior neutral protamine Hagedorn insulin use, a history of fish allergy, or prior vasectomy does not represent a contraindication to protamine administration after cardiopulmonary bypass.

Is lower esophageal contractility a reliable indicator of the adequacy of opioid anesthesia?

Assessing the adequacy of anesthesia in the patient who is without neuromuscular blockade is usually based on somatic as well as sympathetic and hemodynamic responses to stimulation. Because somatic responses are lost in the patient with neuromuscular blockade, a method is needed to replace these signs as an indicator of inadequate anesthesia. This study attempted to determine the relationship between lower esophageal contractility and somatic signs in detecting inadequate fentanyl anesthesia in 20 patients who were undergoing coronary artery surgery and who were hemodynamically stable in the preoperative period. Premedication included midazolam, 0.05 mg/kg intramuscularly, and ranitidine, 2 mg/kg orally. Anesthesia was induced with fentanyl, 50 micrograms/kg, and maintained by an infusion of fentanyl, 0.2 microgram.kg-1.min-1. After endotracheal intubation, a disposable 24-F esophageal monitoring probe equipped with provoking and measuring balloons was inserted, and both the amplitude of provoked and the rate of spontaneous lower esophageal contractions were displayed and recorded. Inadequate anesthesia was indicated by defined somatic signs in response to noxious stimulation. The presence of these responses was correlated with the amplitude of the provoked and the rate of the spontaneous contractions at five specific times during the period preceding initiation of cardiopulmonary bypass. A total of 208 episodes of stimulation were recorded: at insertion of the nasal temperature probe (n = 8), at skin penetration by towel clips (n = 25), at skin incision (n = 20), at sternotomy (n = 20), and during multiple episodes of electrocauterization (n = 135). These provoked 23 somatic responses. The fentanyl concentration in plasma of the 20 patients during the study period was 30 +/- 10 ng/ml (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence of Cell-Saver contamination during cardiopulmonary bypass.

During regular bacteriological surveillance of cardiac surgical equipment and patients, the Cell Saver apparatus (CSA) was prospectively evaluated to determine if it represented an additional risk for infection. Nineteen patients were studied. After each operation, the effluent from the CSA was sterilely sealed for subsequent culture. A total of 42 aerobic and 42 anaerobic cultures were made. Postoperatively all patients were evaluated daily for four days and before discharge for clinical evidence of infection. Four patients had positive CSA cultures without evidence of postoperative clinical infection. Five patients in whom postoperative infectious complications developed had negative CSA cultures. Ten patients had negative CSA cultures and no evidence of postoperative infection. We conclude that the CSA does not appear to contribute to the risk of infection in cardiac surgical patients and that it is a safe adjunct to cardiac surgery.