Drew A. MacGregor

Pharmacokinetics of dopamine in healthy male subjects.

Background Dopamine is an agonist of &agr;, &bgr;, and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model. Methods Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 &mgr;g · kg−1 · min−1 for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 &mgr;g · kg−1 · min−1 for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine. Results Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 &mgr;g · kg−1 · min−1. Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-&mgr;g · kg−1 · min−1 infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion. Conclusions Despite a homogeneous population of healthy male subjects and weight-based dosing, there was 10- to 75-fold intersubject variability in plasma dopamine concentrations, making standard pharmacokinetic modeling of less utility than for other drugs. The data suggest marked intraindividual and interindividual variability in dopamine distribution and/or metabolism. Thus, plasma dopamine concentrations in patients receiving dopamine infusion at identical rates may vary profoundly. Our data suggest that dosing dopamine based on body weight does not yield predictable blood concentrations.

Nosocomial Pneumonia Risk and Stress Ulcer Prophylaxis: A Comparison of Pantoprazole vs Ranitidine in Cardiothoracic Surgery Patients

BACKGROUND Stress ulcer prophylaxis (SUP) using ranitidine, a histamine H2 receptor antagonist, has been associated with an increased risk of ventilator-associated pneumonia. The proton pump inhibitor (PPI) pantoprazole is also commonly used for SUP. PPI use has been linked to an increased risk of community-acquired pneumonia. The objective of this study was to determine whether SUP with pantoprazole increases pneumonia risk compared with ranitidine in critically ill patients. METHODS The cardiothoracic surgery database at our institution was used to identify retrospectively all patients who had received SUP with pantoprazole or ranitidine, without crossover between agents. From January 1, 2004, to March 31, 2007, 887 patients were identified, with 53 patients excluded (pantoprazole, 30 patients; ranitidine, 23 patients). Our analysis compared the incidence of nosocomial pneumonia in 377 patients who received pantoprazole with 457 patients who received ranitidine. RESULTS Nosocomial pneumonia developed in 35 of the 377 patients (9.3%) who received pantoprazole, compared with 7 of the 457 patients (1.5%) who received ranitidine (odds ratio [OR], 6.6; 95% confidence interval [CI], 2.9 to 14.9). Twenty-three covariates were used to estimate the probability of receiving pantoprazole as measured by propensity score (C-index, 0.77). Using this score, pantoprazole and ranitidine patients were stratified according to their probability of receiving pantoprazole. After propensity adjusted, multivariable logistic regression, pantoprazole treatment was found to be an independent risk factor for nosocomial pneumonia (OR, 2.7; 95% CI, 1.1 to 6.7; p = 0.034). CONCLUSION The use of pantoprazole for SUP was associated with a higher risk of nosocomial pneumonia compared with ranitidine. This relationship warrants further study in a randomized controlled trial.

Dobutamine antagonizes epinephrine's biochemical and cardiotonic effects: Results of an in vitro model using human lymphocytes and a clinical study in patients recovering from cardiac surgery

Background Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects. Methods The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobutamine (10‐8 to 10‐4 M) or epinephrine (10‐9 M to 10‐5 M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 [micro sign]g [middle dot] kg‐1 [middle dot] min‐1) or epinephrine (10, 20, or 40 ng [middle dot] kg‐1 [middle dot] min‐1), alone or in combination. Results In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration [almost equal to] 200%. However, when epinephrine (10‐6 M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10‐6 to 10‐4 M (P = 0.001). In patients, 1.25 to 5 [micro sing]g [middle dot] kg‐1 [middle dot] min‐1 dobutamine increased the cardiac index (CI) 15–28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5 [micro sign]g [middle dot] kg‐1 [middle dot] min‐1) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 [micro sign]g [middle dot] kg‐1 [middle dot]‐1 min (‐1)). In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects. Conclusions Dobutamine inhibits epinephrine‐induced production of cAMP in human lymphocytes and appears to be subadditive by clinical and isobolographic analyses of the cardiotonic effects. These findings suggest that combinations of dobutamine and epinephrine may be less than additive.

Late presentation of esophageal injury after transesophageal echocardiography.

Esophageal injury is a rare complication of intraoperative transesophageal echocardiography (TEE) associated with cardiac surgery. We report two cases of delayed presentation (2 and 6 days after surgery) of esophageal injury that were likely due to TEE. The differential diagnosis of postoperative pleural effusion or anemia must include esophageal injury from TEE, even 6 days after the procedure.

A Laboratory Comparison of Three Pulmonary Artery Oximetry Catheters

BackgroundMeasurement of mixed venous hemoglobin oxygen saturation via catheters employing reflectance spectrophotometry has been available for more than 10 yr. Despite numerous clinical reports that have presented data showing the poor accuracy of these devices when used clinically, they are still widely used in clinical care. The reason for lack of agreement with measurements made using bench spectrophotometry is unclear. The purpose of this study is to define the performance limitations of three hemoglobin oxygen saturation catheters (Oximetrix 3, SAT-2, and HEMOPRO2) in a controlled laboratory environment using a blood flow loop primed with fresh whole human blood as a model. Our hypothesis is that the performance limitations of these devices represent inherent limitations in the technology, not error introduced by patient anatomy and physiology. MethodsBlood was equilibrated in a flow loop to four analytic gas mixtures designed to achieve oxygen saturation of approximately 50%, 60%, 70%, and 80%, respectively, with carbon dioxide tension, pH, and temperature held constant. Saturation readings from the catheters were collected on-line by microcomputer. Periodic blood samples were withdrawn from the flow loop for analysis on a bench spectrophotometer and subsequent comparison with catheter-derived values. ResultsBy all measures, performances of the Oximetrix 3 and SAT-2 systems were comparable (all data are presented as percent saturation unless otherwise noted); bias ± precision was 3.20 ± 2.47 and −1.25 ± 3.36, respectively, versus −9.97 ± 7.05 for the HEMOPRO2. The 95% confidence limits based on intracatheter variability were ±3.49, ±2.90, and ±9.13 for the Oximetrix 3, SAT-2, and HEMOPRO2, respectively. The 95% confidence limits based on total variability, although similar for Oximetrix 3 (±4.83) and SAT-2 (±6.59), were larger for the HEMOPRO2 (±13.82). The 95% confidence Intervals for agreement between catheter brands were −2.14, 11.04 (Oximetrix 3 – SAT-2); −0.18, 26.52 (Oximetrix 3 – HEMOPRO2) and −5.24, 22.68 (SAT-2 – HEMOPRO2). ConclusionsWhile the Oximetrix 3 and SAT-2 may be acceptable as continuous monitors used to detect changes or trends, none of the three systems is equivalent to conventional bench oximetry for the measurement of hemoglobin oxygen saturation.

Chest wall rigidity during infusion of fentanyl in a two-month-old infant after heart surgery

Chest wall rigidity (0%~) is a common complication of potent opioids given as bolus injections, most often as anesthetic induction agents. Fentanyl is a synthetic opioid agonist that is approximately 100 times more potent than morphine. When given as a small bolus injection, fentanyl 100 pg has been reported to cause CWR in an adult.’ Reports of CWR in infants are beginning to emerge as clinicians’ interests increase in providing sedation and analgesia in critically ill infants and children. Recognition that routine procedures on critically ill infants (venipunctures, endotracheal suctioning) are associated with sudden increases in blood pressure and intracranial pressure, and occasionally acute increases in pulmonary vascular resistance with profound hypoxia, has prompted the increased utilization of sedative agents and narcotics in the intensive care unit (ICU).’ Opiates such as meperidine, morphine, fentanvl, and alfentanil have been used for sedation of mechan&-ally ventilated neonates but CWR has not been reported with a low dose continuous infusion of

Training internists to meet critical care needs in the United States: A consensus statement from the critical care societies collaborative (CCSC)

Objectives:Multiple training pathways are recognized by the Accreditation Council for Graduate Medical Education (ACGME) for internal medicine (IM) physicians to certify in critical care medicine (CCM) via the American Board of Internal Medicine. While each involves 1 year of clinical fellowship training in CCM, substantive differences in training requirements exist among the various pathways. The Critical Care Societies Collaborative convened a task force to review these CCM pathways and to provide recommendations for unified and coordinated training requirements for IM-based physicians. Participants:A group of CCM professionals certified in pulmonary-CCM and/or IM-CCM from ACGME-accredited training programs who have expertise in education, administration, research, and clinical practice. Data Sources and Synthesis:Relevant published literature was accessed through a MEDLINE search and references provided by all task force members. Material published by the ACGME, American Board of Internal Medicine, and other specialty organizations was also reviewed. Collaboratively and iteratively, the task force reached consensus using a roundtable meeting, electronic mail, and conference calls. Main Results:Internal medicine-CCM–based fellowships have disparate program requirements compared to other internal medicine subspecialties and adult CCM fellowships. Differences between IM-CCM and pulmonary-CCM programs include the ratio of key clinical faculty to fellows and a requirement to perform 50 therapeutic bronchoscopies. Competency-based training was considered uniformly desirable for all CCM training pathways. Conclusions:The task force concluded that requesting competency-based training and minimizing variations in the requirements for IM-based CCM fellowship programs will facilitate effective CCM training for both programs and trainees.

VARIABILITY IN CENTRAL VENOUS PRESSURE MEASUREMENTS AND THE POTENTIAL IMPACT ON FLUID MANAGEMENT

In the intensive care unit (ICU) of our tertiary care university medical center, central venous pressure (CVP) measurements derived from bedside monitors differ considerably from measurements by trained intensivists using paper tracings. To quantify these differences, printed CVP tracings and concurrent respiratory waveforms were collected from 100 consecutive critically ill patients along with the corresponding monitor-displayed CVP. Four blinded intensivists interpreted the tracings. The mean difference between the intensivists and the monitor was −0.26 mmHg (95% confidence interval, +7.19 to −7.71 mmHg). Seventy-six percent of the paired measurements were within 2 mmHg, whereas 7% differed by more than 5 mmHg. To determine the potential clinical impact of these differences, we used the original Surviving Sepsis Campaign Guidelines for fluid administration based upon the measurement of CVP. For individual physicians, protocol-driven fluid management strategy would have differed in 19.2% to 25.3% of cases, dependent upon which measured value was chosen. Although protocol-driven strategies to direct fluid infusion therapy may improve outcomes, these interventions in a specific patient are dependent upon the method by which the CVP is measured.

Pulmonary artery catheter placement for elective coronary artery bypass grafting: Before or after anesthetic induction?

UNLABELLED Pulmonary arterial catheters (PACs) are often used during and after coronary artery bypass grafting. We hypothesized that placement of a PAC would be faster in anesthetized patients. We further hypothesized that the presence or absence of a PAC during the induction of anesthesia would make no difference in hemodynamics, vasoactive drug use, or IV fluid administration during the induction. Patients (n = 200) undergoing elective coronary artery bypass grafting were assigned to PAC insertion either before or after the induction of anesthesia. Total time for PAC insertion, number of finder needle and venous catheter insertion attempts, incidence of carotid artery puncture, arrhythmias or ST segment changes, arterial blood gas analysis, hemodynamic variables, IV fluids, and vasoactive drugs required during and after the anesthetic induction were recorded. Thirty-two different physicians placed the PACs. PAC placement was faster (10 versus 12 min, P = 0.0003) and required fewer punctures with a finder needle (P = 0.0107) in anesthetized patients. There were no significant differences between groups in hemodynamic values or use of vasoactive or anesthetic drugs or IV fluids during the induction. There were also no significant differences between groups in the incidence of myocardial ischemia, arterial hypoxemia, or hypercarbia. Placement of a PAC before the induction of anesthesia consumes more time and fails to improve hemodynamic stability or lessen vasoactive drug use during the induction of anesthesia. IMPLICATIONS Insertion of pulmonary artery catheters (PACs) before the induction of anesthesia requires more needle sticks and takes longer than insertion after the induction of anesthesia; moreover, previous PAC insertion has no significant effect on hemodynamics or use of vasoactive drugs or IV fluid associated with the induction of anesthesia.

Dose response, recovery, and cost of doxacurium as a continuous infusion in neurosurgical intensive care unit patients

OBJECTIVES To determine the optimal dosing of doxacurium as a continuous infusion in neurosurgical patients with traumatic brain injury; to determine the effects of bolus administration of doxacurium on heart rate (HR), blood pressure (BP), and intracranial pressure (ICP); to monitor neuromuscular recovery after discontinuation of prolonged doxacurium infusion; and to compare the cost of doxacurium with other current neuromuscular blocking drugs. DESIGN Prospective, open-label study. SETTING Neurosurgical intensive care unit (ICU) of a university-affiliated teaching hospital. PATIENTS Eight critically ill, mechanically ventilated patients with traumatic head injury and normal renal and hepatic function. Patients had ICP monitoring. INTERVENTIONS A bolus injection of doxacurium (0.05 mg/kg) followed by a continuous infusion (0.015 mg/kg/hr), adjusted to maintain one twitch during Train-of-Four nerve stimulation of the adductor pollicis muscle. MEASUREMENTS AND MAIN RESULTS Bolus injections of doxacurium did not alter the HR, BP, or ICP. Patients were paralyzed 66 +/- 12 (SEM) hrs, with recovery of the fourth twitch occurring 118 +/- 19 mins after infusion of the doxacurium was discontined. There were no incidences of prolonged weakness, myopathy, or other adverse events. CONCLUSIONS Continuous infusion of doxacurium provides stable neuromuscular blockade for neurosurgical patients with traumatic brain injury. Doxacurium is devoid of clinically important interactions with HR, BP, or ICP and is less costly than other neuromuscular blockers used in the ICU.