Roberta L. Hines

Pharmacology and Biological Efficacy of a Recombinant, Humanized, Single-Chain Antibody C5 Complement Inhibitor in Patients Undergoing Coronary Artery Bypass Graft Surgery With Cardiopulmonary Bypass

BACKGROUND Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB. METHODS AND RESULTS A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0. 05) in patients who received 1 or 2 mg/kg. CONCLUSIONS A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.

Complications occurring in the postanesthesia care unit: a survey.

To identify and quantitate complications occurring in the postanesthesia care unit (PACU), a prospective study evaluated 18,473 consecutive patients entering a PACU at a university teaching hospital. Using a standardized collection form, the incidence of intra-operative and PACU complications was determined. The combined PACU and intraoperative complication rate was 26.7%. Data showed a PACU complication rate of 23.7%, with an overall intraoperative complication rate of 5.1%. Nausea and vomiting (9.8%), the need for upper airway support (6.9%), and hypotension requiring treatment (2.7%) were the most frequently encountered PACU complications. Patients in whom PACU complications developed were analyzed by ASA physical status. Of all patients experiencing nausea and vomiting (n = 1571), the highest percentage were ASA physical status II patients (n = 831). Likewise, in the group of 1450 patients who demonstrated a need for upper airway support, 792 were ASA physical status II. In patients experiencing a major cardiovascular complication, for example, variables associated with a greater risk of developing any PACU complications were ASA physical status (status II), duration of anesthesia (2–4 h), anesthetic technique, emergency procedures, and certain types of surgical procedures (orthopedic or abdominal). For patients admitted with a temperature of < 35°C the duration of the PACU stay was 152 ± 46 min compared with 116 ± 65 min for patients with a temperature ≥36°C (P < 0.01). In conclusion, events occurring during the PACU period continue to be a source of patient morbidity.

A Pharmacokinetic and Pharmacodynamic Evaluation of Milrinone in Adults Undergoing Cardiac Surgery

Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients.Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 micro gram/kg) in an openlabel, dose-escalating study if their cardiac index was <3 L centered dot min-1 centered dot m-2 after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices <3 L centered dot min-1 centered dot m-2 after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-micro gram/kg doses produced significantly larger increases in cardiac index than the 25-micro gram/kg dose; however, the 75-micro gram/kg dose did not produce a significantly larger increase in cardiac index than did the 50-micro gram/kg dose. Two of 10 patients receiving milrinone 25 micro gram/kg, but no patient receiving either 50 or 75 micro gram/kg, required early epinephrine rescue when the cardiac index failed to increase by >15%. The 75-micro gram/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-micro gram/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V (1) = 11.1 L, V2 = 16.9 L, and V3 = 363 L. Similarly, the following clearances were estimated for the three compartments: Cl1 = 0.067 L/min, Cl2 = 1.05 L/min, and Cl3 = 0.31 L/min. The 50-micro gram/kg loading dose appeared more potent than the 25-micro gram/kg dose, and, as potent, but with possibly fewer side-effects than the 75-micro gram/kg dose. The short context-sensitive half-times of 6.7 or 10.2 min after 1- or 10-min bolus infusions underscore the need for prompt institution of a maintenance infusion when milrinone concentrations must be maintained. Simulations based on our best drug disposition using this studys variables predict a context-sensitive half-time of 4.9 h for plasma milrinone concentrations after a 50-micro gram/kg bolus 1-min infusion with an immediate 24-h maintenance infusion of 0.5 micro gram centered dot min-1 centered dot kg-1. (Anesth Analg 1995;81:783-92)

Management of chronic pain in the elderly: focus on transdermal buprenorphine

Chronic pain in the elderly is a significant problem. Pharmacokinetic and metabolic changes associated with increased age makes the elderly vulnerable to side effects and overdosing associated with analgesic agents. Therefore the management of chronic cancer pain and chronic nonmalignant pain in this growing population is an ongoing challenge. New routes of administration have opened up new treatment options to meet this challenge. The transdermal buprenorphine matrix allows for slow release of buprenorphine and damage does not produce dose dumping. In addition the long-acting analgesic property and relative safety profile makes it a suitable choice for the treatment of chronic pain in the elderly. Its safe use in the presence of renal failure makes it an attractive choice for older individuals. Recent scientific studies have shown no evidence of a ceiling dose of analgesia in man but only a ceiling effect for respiratory depression, increasing its safety profile. It appears that transdermal buprenorphine can be used in clinical practice safely and efficaciously for treating chronic pain in the elderly.

Mannitol and dopamine in patients undergoing cardiopulmonary bypass: a randomized clinical trial.

In this prospective, randomized, placebo-controlled, double-blinded study, we determined the effects of two commonly used adjuncts, mannitol and dopamine, on &bgr;2-microglobulin (&bgr;2M) excretion rates in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). &bgr;2M excretion rate has been described as a sensitive marker of proximal renal tubular function. One-hundred patients with a preoperative serum creatinine level ≤1.5 mg/dL were prospectively randomized into 4 groups: 1) placebo, 2) mannitol 1 g/kg added to the CPB prime, 3) dopamine 2 &mgr;g · kg−1 · min−1 from the induction of anesthesia to 1 h post-CPB, or 4) mannitol plus dopamine. The primary outcome measure was &bgr;2M excretion rate at 1 h post-CPB. Secondary outcome measures included &bgr;2M excretion rate at 6 and 24 h post-CPB; urinary flow rate and creatinine clearance at 1, 6, and 24 h post-CPB; and the highest postoperative serum creatinine level. Length of intensive care stay and hospitalization, as well as adverse events, were also considered secondary outcomes. Dopamine significantly increased &bgr;2M excretion rate at 1 h post-CPB (2.48 ± 3.61 &mgr;g/min) compared with placebo (0.59 ± 1.04 &mgr;g/min; P = 0.001). This effect was not ameliorated by the addition of mannitol (&bgr;2M excretion rate, 2.05 ± 2.77 &mgr;g/min; P = 0.007 compared with placebo). &bgr;2M excretion rate was similar in patients given placebo or mannitol alone (P = 0.831). Rather than being a protective drug in the setting of CPB, dopamine alone or in combination with mannitol increases &bgr;2M excretion rate, which may be a measure of renal tubular dysfunction. The clinical implications of this increase and whether it is also seen in patients with established renal dysfunction undergoing CPB require additional investigation.

Infusion of sodium nitroprusside induces platelet dysfunction in vitro

The effect of sodium nitroprusside (SNP) infusion on platelet function was prospectively evaluated in 29 patients undergoing cardiac surgical procedures requiring cardiopulmonary bypass. Any patient receiving preoperative medication known to interfere with platelet function was excluded from this study. Platelet function was evaluated by measurement of platelet aggregation with both adenosine diphosphate (ADP) and epinephrine-induced aggregation tests. Ten patients served as a control population receiving fentanyl anesthesia and no SNP. Nineteen patients received SNP, as clinically indicated, following the induction of anesthesia (and prior to cardiopulmonary bypass) to maintain a mean blood pressure of 80 mmHg. The infusion rate and total dose of SNP delivered was recorded for each patient. Infusion rates of SNP greater than or equal to 3 micrograms.kg.-1 min-1 resulted in a dose-related decrease in platelet aggregation (P less than 0.05). This reduction in platelet function was accompanied by a concomitant increase in bleeding time from 5.8 +/- 0.6 to 9.3 +/- 0.4 min in the patients receiving SNP (P less than 0.05). In addition, with the administration of a total dose of SNP greater than or equal to 16 mg, a significant reduction in platelet aggregation (P less than 0.05) was observed. Platelet aggregation studies and bleeding time performed in the control group (following the administration of fentanyl (30 micrograms/kg) did not reveal any deviation from baseline values. The results from this in vivo study support previous in vitro data demonstrating a detrimental effect upon platelet function following SNP infusion.

Acute Pain in Undergraduate Medical Education: An Unfinished Chapter!

Inadequately treated acute pain is a global healthcare problem that causes significant patient suffering and disability, risk of chronicity, increased resource utilization, and escalating healthcare costs. Compounding the problem is the lack of adequate instruction in acute pain management available in medical schools worldwide. Incorporating acute pain diagnosis and management as an integral part of the medical school curriculum will allow physicians to develop a more comprehensive, compassionate approach to treating patients with acute pain syndromes and should be considered a healthcare imperative. In this article, we review the current status of pain education in educational institutions across the world, focusing on achievements, lacunae, and inadequacies. We appeal to all concerned—pain management specialists, health educators, and policymakers—to consider incorporating education on acute pain and its management at undergraduate medical levels in an integrated manner.

Transesophageal two-dimensional echocardiographic analysis of right ventricular systolic performance indices during coronary artery bypass grafting

Sixteen patients (aged 59 +/- 14 years) undergoing coronary artery bypass surgery were evaluated to delineate the intraoperative course of transesophageal echocardiographic right ventricular (RV) systolic performance indices. Pre-induction data included thermodilution RV ejection fraction (RVEFTD), 0.43 +/- 0.13, RV end-diastolic volume index (EDVI), 110 +/- 33 mL/m2, cardiac index (CI), 3.4 +/- 1.0 L/min/m2, RV end-diastolic pressure (EDP), 7.1 +/- 4.2 mmHg, and mean pulmonary artery pressure (PAP), 21 +/- 6 mmHg. Eleven patients had significant right coronary artery (RCA) disease (> 70% occlusion). Five patients arrived with an ongoing nitroglycerin infusion (1 to 3 micrograms/kg/min), which was maintained intraoperatively. Echocardiographic measurements included longitudinal-axis (LA) and short-axis (SA) planimetered area excursion fractions (2DLA and 2DSA, respectively) and LA maximal major and minor axis shortening fractions (max majorLA and max minorLA, respectively). Hemodynamic measurements included RVEFTD, EDVI, CI, EDP, and PAP. Measurements were determined following induction/endotracheal intubation, following sternotomy/pericardiotomy, and after cardiopulmonary bypass (CPB) with the chest open. All patients were maintained on vasodilator therapy post-CPB (nitroglycerin, 1 to 3 micrograms/kg/min [N = 16] and nitroprusside, 0.5 to 4.5 microgram/kg/min [N = 4]) post-CPB. Two patients received inotropic support (epinephrine, 0.2 to 0.3 microgram/kg/min). CPB was associated with significant decreases in max major axisLA and 2DLA (P < 0.05) as compared to measurements determined prior to CPB. Maximum major axisLA values pre-CPB were 0.35 +/- 0.06 and 0.33 +/- 0.08 versus post-CPB values of 0.24 +/- 0.08.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between “Normal” transesophageal color-flow doppler-defined tricuspid regurgitation and thermodilution right ventricular ejection fraction measurements

Twenty coronary artery revascularization patients, aged 58 +/- 15 years, were studied intraoperatively to define the impact of Doppler-defined tricuspid regurgitation on measurement of thermodilution right ventricular ejection fraction (50 msec response pulmonary artery catheter). Right ventricular function was also estimated using a measurement technique independent of flow patterns across the tricuspid valve (transesophageal two-dimensional echocardiographic 5.0 MHz phased-array transducer). Measurements included transverse plane long- and short-axis planimetered area ratio, respectively, and tricuspid annular plane systolic excursion ratio (ratio = end-diastolic minus end-systolic value divided by end-diastolic value). Data were expressed as thermodilution-echocardiographic gradients, ie, thermodilution ejection fraction minus long-axis planimetered area ratio, short-axis planimetered area ratio, and tricuspid annular plane systolic excursion ratio, respectively. Tricuspid regurgitation was quantified by color-flow Doppler perimetry of maximal regurgitation jet area and analysis of transduced right atrial pressure waveform. Doppler estimates were expressed as absolute values and as a function of corresponding atrial area (tricuspid regurgitation index = planimetered jet area divided by right atrial area). Data were obtained following endotracheal intubation, sternotomy, pericardiotomy, cardiopulmonary bypass, and chest closure. Data were evaluated by regression analysis, with separate analyses performed for each time period. Profiles were unassociated with right atrial pressure waveform abnormalities. There was no significant relationship between thermodilution ejection fraction variance values and tricuspid regurgitation jet area or regurgitation index, respectively. In each measurement period, thermodilution-echocardiographic gradients were also unrelated to the tricuspid regurgitation estimates.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroprusside Inhibition of Platelet Function Is Transient and Reversible by Catecholamine Priming

BACKGROUND The time course and reversibility of sodium nitroprussides in vivo inhibition of platelet function are unclear. METHODS Platelet aggregation and P-selectin expression as measures of platelet dense and alpha-granule release, respectively, were examined before and after administration of sodium nitroprusside (18 mg) to human volunteers and in in vitro studies. Hypotension occurring with sodium nitroprusside administration was treated with intravenous crystalloid and/or phenylephrine. RESULTS Compared with preinfusion studies, platelet aggregation to epinephrine was significantly inhibited immediately and 4 min after discontinuation of the sodium nitroprusside infusion but returned to baseline at 8 and 12 min after discontinuing sodium nitroprusside. However, both dense and alpha-granule release to adenosine diphosphate after in vivo sodium nitroprusside were never significantly inhibited even at the time when sodium nitroprusside infusion was maximal. In contrast to our in vivo findings, in vitro incubation of platelet-rich plasma with sodium nitroprusside resulted in significant inhibition of dense and alpha-granule release to adenosine diphosphate. These in vitro inhibitory effects of sodium nitroprusside were reversed by pretreatment with epinephrine but not phenylephrine. CONCLUSIONS In normal volunteers, sodium nitroprusside inhibits platelet aggregation to epinephrine but not adenosine diphosphate; inhibition was reversed within 8-12 min after discontinuing sodium nitroprusside. Sodium nitroprusside in vitro inhibition of platelet function to adenosine diphosphate was reversed by epinephrine pretreatment. Because of the rapid reversibility of its antiplatelet effect, sodium nitroprusside may be clinically useful even when there is the potential for impaired coagulation.