William E. Johnston

Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs.

BackgroundIt has recently been demonstrated that myocardial ischemia and reperfusion results in a marked decrease in the release of nitric oxide (NO) by the coronary endothelium. NO may possess cardioprotective properties, possibly related to inhibition of neutrophil-related activities. We tested the hypothesis that a cysteine-containing nitric oxide donor compound, SPM-5185, would reduce infarct size and inhibit neutrophil-related activities (adherence to coronary vascular endothelium, accumulation). Methods and ResultsThe effects of intracoronary infusion of SPM-5185 were investigated in a 5.5-hour model of myocardial ischemia (1 hour) and reperfusion (4.5 hours) (MI-R) in anesthetized, open-chest dogs. SPM-5185 (500 nmol/L) or saline vehicle was infused for 4.5 hours into the left anterior descending coronary artery (LAD) at the time of reperfusion after 1 hour of LAD occlusion. MI-R in dogs receiving saline vehicle resulted in severe myocardial injury characterized by dyskinesis, a profound elevation of plasma creatine kinase, marked myocardial necrosis, and high cardiac myeloperoxidase (MPO) activity in the ischemic and necrotic zones. In contrast, treatment with SPM-5185 resulted in a modest restoration of regional function, a reduction of myocardial necrosis expressed as a percentage of the area at risk (12.5±3.2% versus 41.7±5.4%, P<.001), and significant reductions of MPO activity in the ischemic zone (0.8±0.1 versus 2.5±0.7 U/100 mg tissue, P<.05) and the necrotic zone (1.6±0.2 versus 3.3±0.6 U/100 mg tissue, P<.05). In additional studies, SPM-5185 (500 nmol/L) significantly (P<.001) attenuated the adherence of LTB4-stimulated canine neutrophils to autologous segments of coronary artery and attenuated the neutrophil-induced contraction of isolated coronary arterial rings. ConclusionsSPM-5185 reduces myocardial necrosis and neutrophil accumulation in an acute model of canine myocardial ischemia and reperfusion. This reduction in myocardial cell injury may be partially related to the inhibitory actions of this novel NO donor on neutrophil adherence to the coronary endothelium.

Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia.

BackgroundWe hypothesized that 1) endogenous adenosine released during ischemia conferred an inherent cardioprotection, and 2) a pretreatment dose of adenosine before ischemia would provide additional protection independent of hemodynamic effects. Methods and ResultsThirty-six anesthetized New Zealand White rabbits underwent 30 minutes of regional ischemia produced by coronary occlusion followed by 2 hours of reperfusion. The adenosine group (ADO, n=9) received a 5-minute pretreatment infusion of 140 pg/kg/min of adenosine before ischemia. A control group (SAL, n=9) received saline before ischemia. To separate the effects of adenosine used as a pretreatment versus the effects during ischemia, a third group (ADO+SPT, n=9) received adenosine as pretreatment followed by 10 mg/kg 8-p-sulfophenyl theophylline (8-SPT), an A1/A2-receptor antagonist given before ischemia, thus allowing pretreatment with adenosine but antagonizing its effects during ischemia. To preclude any protection from endogenous adenosine released during ischemia, the fourth group (SAL+SPT, n=9) received saline as pretreatment and 8-SPT before ischemia. Area of necrosis within the area at risk (infarct size) was determined with tetrazolium and Evans blue stains, and transmural blood flow was measured using radioactive microspheres. Collateral blood flow in the area at risk was similar in all groups, as was the size of the area at risk. Infarct size was reduced by adenosine pretreatment (ADO, 8A±47.2%) in contrast to saline vehicle (SAL, 27.8±63%; p<0.05 versus ADO). α1/α2-Receptor blockade after adenosine pretreatment abolished the ischemic protection provided by pretreatment adenosine (ADO+SPT, 42.7±83%; p<0.05 versus ADO). Finally, receptor blockade of endogenously released adenosine without adenosine pretreatment increased infarct size by 24% over the nonpretreated saline group (SAL+SPT, 51.5±9.00%; p<0.05 versus SAL). ConclusionsWe conclude that 1) endogenous adenosine building up during ischemia is cardioprotective, and 2) pretreatment with adenosine confers cardioprotection independent of hemodynamic effects. Whether pretreatment effects of adenosine subsequently modulate the effects of endogenous adenosine (through alterations in receptor population or sensitivity) or endogenous and exogenous adenosine represent additive compartments is unclear.

Effects on intracranial pressure of resuscitation from hemorrhagic shock with hypertonic saline versus lactated Ringer's solution.

Hypertonic saline (2400 mOsm/L) has been used successfully for fluid resuscitation of dogs subjected to severe hemorrhagic shock. This study compared the effects of resuscitation with hypertonic saline vs. lactated Ringers solution on intracranial pressure (ICP) in dogs subjected to 30 min of sustained hypovolemic shock. Hypotension was produced by rapid withdrawal of blood until mean arterial pressure was 50 mm Hg, maintained at that level by withdrawal or infusion of blood over the next 30 min as necessary. Eight animals were resuscitated with hypertonic saline solution and nine with lactated Ringers solution. Both solutions restored systolic blood pressure and cardiac output to control values. However, diastolic blood pressure and mean arterial pressure did not return to control values. The most prominent difference between the two groups was in ICP measured after resuscitation. ICP was lower in dogs resuscitated with hypertonic saline than in dogs resuscitated with lactated Ringers solution (p = .029). Hypertonic saline fluid resuscitation may represent a potential alternative when aggravation of intracranial hypertension during resuscitation would place a patient at greater risk.

Regional Perfusion Abnormalities With Phenylephrine During Normothermic Bypass

BACKGROUND Hypotension and vasopressors during cardiopulmonary bypass may contribute to splanchnic ischemia. The effect of restoring aortic pressure on visceral organ, brain, and femoral muscle perfusion during cardiopulmonary bypass by increasing pump flow or infusing phenylephrine was examined. METHODS Twelve anesthetized swine were stabilized on normothermic cardiopulmonary bypass. After baseline measurements, including regional blood flow (radioactive microspheres), aortic pressure was reduced to 40 mm Hg by decreasing the pump flow. Next, aortic pressure was restored to 65 mm Hg either by increasing the pump flow or by titrating phenylephrine. The animals had both interventions in random order. RESULTS At 40 mm Hg aortic pressure, perfusion to all visceral organs and femoral muscle, but not to the brain, was significantly reduced. Increasing pump flow improved perfusion to the pancreas, colon, and kidneys. In contrast, infusing phenylephrine (2.4 +/- 0.6 micrograms.kg-1.min-1) increased aortic pressure but failed to improve splanchnic perfusion, so that significant perfusion differences existed between the pump flow and phenylephrine intervals. CONCLUSIONS Increasing systemic pressure during cardiopulmonary bypass with phenylephrine causes significantly lower values of splanchnic blood flow than does increasing the pump flow. Administering vasoconstrictors during normothermic cardiopulmonary bypass may mask substantial hypoperfusion of splanchnic organs despite restoration of perfusion pressure.

Preoperative and intraoperative predictors of inotropic support and long-term outcome in patients having coronary artery bypass grafting.

The prognostic value of preoperative symptoms, preoperative left ventricular function, and intraoperative factors as related to postoperative outcome in coronary artery bypass grafting is unclear. This study was performed to identify risk factors that could be used as markers to predict immediate and long-term outcome, knowledge of which might allow physicians to modify these factors to decrease the likelihood of an adverse outcome. We retrospectively evaluated preoperative factors (including age, sex, New York Heart Association [NYHA] classification of symptoms, ejection fraction [EF], wall motion abnormalities, baseline left ventricular end-diastolic pressure [LVEDP], postradiographic contrast infection LVEDP, change in LVEDP with contrast injection, cardiac enlargement, and collateral vessels) and intraoperative factors (duration of bypass and aortic cross-clamp time) in 128 patients. The need for inotropic drug support was used as a marker of immediate outcome. A 36-mo follow-up used death and the postoperative NYHA classification of symptoms as markers of long-term outcome. The various factors associated with the use of inotropes and immediate outcome were analyzed by logistic regression. The factors related to inotrope use (and presumed adverse short-term outcome) in order of decreasing significance were lower EF, older age, cardiac enlargement, female sex, and higher baseline and postcontrast LVEDP. Patients with EF s 55%, but also having wall motion abnormalities and LVEDP change ≥ 10 mm Hg, and all patients with EF ≥ 55% were more likely to require inotropic drug stimulation after cardiopulmonary bypass. Neither the change in LVEDP nor the presence of wall motion abnormalities independently predicted the need for postoperative inotropic support. Analysis of long-term outcome in 113 patients revealed an improvement in mean NYHA score from 2.8 ± 0.9 (mean ± SD) preoperatively to 1.6 ± 0.7 postoperatively. Those factors that predicted a worse long-term outcome (defined as higher postoperative NYHA scores or death) were higher preoperative NYHA scores, older age, female sex, and prolonged duration of cardiopulmonary bypass. Only 5 of 113 patients had died at the 36-mo follow-up, precluding statistical analysis of mortality. In contrast to randomized trials of oral inotropic agents in chronic congestive heart failure, in this study the perioperative use of inotropes (our marker of immediate outcome) was only marginally predictive of a less favorable long-term outcome.

Hemodynamic and cardiac contractile function during sepsis caused by cecal ligation and puncture in mice

Sepsis is among the leading causes of death in the critically ill, yet the pathophysiology of sepsis is incompletely understood. Genetically engineered mice offer a unique opportunity to explore the cellular and molecular pathogenesis of sepsis. However, the hemodynamic responses of mice during sepsis are not completely understood because of the difficulty in performing cardiovascular measurements in mice. We used a 1.4-F pressure and conductance catheter to measure hemodynamics in wild-type C57BL/6J mice during sepsis caused by cecal ligation and puncture. Septic mice exhibited significant hypothermia compared with the sham group. In addition, there was a progressive decrease in mean arterial blood pressure and systemic vascular resistance in septic mice as well as an increase in stroke volume and cardiac output. Sepsis also caused a significant time-dependent impairment of left ventricular function as indicated by decreased dp/dtmax and dp/dtmin. The slope of end systolic pressure volume relationship also decreased over time, as did the time varying maximum elastance and preload-recruitable stroke work of the left ventricle. In conclusion, septic mice exhibit hemodynamic alterations during sepsis that are similar to those observed in humans. The miniaturized conductance catheter allows for effective measurements of hemodynamic function in septic mice and provides measurements that cannot be obtained using other cardiovascular monitoring techniques.

Increasing organ blood flow during cardiopulmonary bypass in pigs : comparison of dopamine and perfusion pressure

OBJECTIVE To determine whether low-dose dopamine infusion (5 micrograms/kg/min) during cardiopulmonary bypass selectively increases perfusion to the kidney, splanchnic organs, and brain at low (45 mm Hg) as well as high (90 mm Hg) perfusion pressures. DESIGN Randomized crossover trial. SETTING Animal research laboratory in a university medical center. SUBJECTS Ten female Yorkshire pigs (weight 29.9 +/- 1.2 kg). INTERVENTION Anesthetized pigs were placed on normothermic cardiopulmonary bypass at a 100-mL/kg/min flow rate. After baseline measurements, the animal was subjected, in random sequence, to 15-min periods of low perfusion pressure (45 mm Hg), low perfusion pressure with dopamine (5 micrograms/kg/min), high perfusion pressure (90 mm Hg), and high perfusion pressure with dopamine. Regional perfusion (radioactive microspheres) was measured in tissue samples (2 to 10 g) from the renal cortex (outer two-third and inner one-third segments), stomach, duodenum, jejunum, ileum, colon, pancreas, and cerebral hemispheres. MEASUREMENTS AND MAIN RESULTS Systemic perfusion pressure was altered by adjusting pump flow rate (r2 = .61; p < .05). In the kidney, cortical perfusion pressure increased from 178 +/- 16 mL/min/100 g at the low perfusion pressure to 399 +/- 23 mL/min/100 g at the high perfusion pressure (p < .05). Perfusion pressure augmentation increased the ratio of outer/inner renal cortical blood flow from 0.9 +/- 0.1 to 1.2 +/- 0.1 (p < .05). At each perfusion pressure, low-dose dopamine had no beneficial effect on renal perfusion or flow distribution. Similar results were found in the splanchnic organs, where regional perfusion was altered by perfusion pressure but not by dopamine. In contrast, neither changing perfusion pressure nor adding low-dose dopamine altered blood flow to the cerebral cortex. CONCLUSIONS These data indicate that the lower autoregulatory limits of perfusion to the kidneys and splanchnic organs differ from those limits to the brain during normothermic bypass. Selective vasodilation from low-dose dopamine was not found in renal, splanchnic, or cerebral vascular beds. Increasing the perfusion pressure by pump flow, rather than by the addition of low-dose dopamine, enhanced renal and splanchnic but not cerebral blood flows during cardiopulmonary bypass.

Technique of controlled reperfusion of the transplanted lung in humans

BACKGROUND Reperfusion injury remains a significant and sometimes fatal problem in clinical lung transplantation. Controlled reperfusion of the transplanted lung using white cell-filtered, nutrient-enriched blood has been shown recently to significantly ameliorate reperfusion damage in a porcine model. We modified this experimental technique and applied it to human lung transplantation. METHODS Approximately 1,500 mL of arterial blood was slowly collected in a cardiotomy reservoir during the lung implant, and mixed to make a 4:1 solution of blood:modified Buckberg perfusate. This solution was passed through a leukocyte filter and into the transplant pulmonary artery for 10 minutes, at a controlled rate (200 mL/min) and pressure (less than 20 mm Hg), immediately before removal of the vascular clamp. RESULTS Five patients underwent lung transplantation (1 bilateral, 4 single lung) using this technique. All patients were ventilated on a 40% fraction of inspired oxygen within a few hours and extubated on or before the first postoperative day. CONCLUSIONS Controlled reperfusion of the transplanted lung with white cell-filtered, nutrient-enriched blood has given excellent functional results in our small initial clinical series.

Controlled coronary hydrodynamics at the time of reperfusion reduces postischemic injury

Background: In a canine preparation of 2 hours of coronary occlusion and 2 hours of reperfusion, we tested the hypothesis that controlled hydrodynamic conditions (coronary pressure and flow) of reperfusion would decrease infarct size and improve regional functional recovery. Methods: In 28 anesthetized, open-chest dogs, segmental contractile work and diastolic stiffness (sonomicrometry), and myocardial blood flow (15 μm microspheres) were measured in the segment per fused by the left anterior descending (LAD) and circumflex coronary arteries. After 2 hours of LAD occlusion, reperfusion was established using an extracorporeal perfusion circuit to control intracoronary pressure and blood flow. Twelve dogs did not complete the protocol or meet exclusion criteria. In eight dogs (abrupt group), blood flow was abruptly restored and continued for 2 hours of reperfusion. In eight dogs (ramp group), blood flow was adjusted so that LAD perfusion pressure was linearly incremented over the first 30 minutes of reflow, and equalized to mean arterial pressure thereafter. Results: Two hours of LAD occlusion reduced myocardial blood flow in the ischemic zone from 67.7 ± 11.7 to 11.7 ± 4.7 mL/min/100g (P Conclusions: Slowly increasing coronary pressure and blood flow during the early phase of reperfusion 1) increases postischemic systolic and diastolic functional recovery, 2) improves postischemic blood flow, and 3) reduces infarct size by 67%. These data suggest that the mode of reperfusion may be a factor in determining myocardial injury after reversible occlusion.

The prevalence and characteristics of incentive plans for clinical productivity among academic anesthesiology programs

Performance-based compensation is encouraged in medical schools to improve faculty productivity. Medical specialties other than anesthesiology have used financial incentives for clinical work. The goal of this study was to determine the prevalence and the types of clinical incentive plans among academic anesthesiology departments. We performed an electronic survey of the members of the Society of Academic Anesthesiology Chairs and the Association of Anesthesiology Program Directors in the spring of 2003. The survey included questions about departmental size, presence of a clinical incentive plan, characteristics of existing incentive plans, primary quantifiers of productivity, and factors used to modify productivity measurements. An incentive plan was considered to be present if the department measured clinical productivity and varied compensation according to the measurements. The plans were grouped by the primary measure used into the following categories: None, Charges, Time, Shift, Late/Call (only late rooms and call), and Other. Eighty-eight (64%) of 138 programs responded to the survey, and 5 were excluded for incomplete data. Of the responding programs, 29% had no system, 30% used a Late/Call system, 20% used a Shift system, 11% used a Charges system, 6% used a Time system, and 3% fit in the Other category. Larger groups (>40 faculty members) had a significantly more frequent prevalence of incentive plans compared with smaller groups (<20 faculty members). Incentives were paid monthly or quarterly in 85% of the groups. In 90% of groups, incentive payments accounted for <25% of total compensation. Adjustments for operating room schedule supervisors, personally performed cases, day surgery preoperative clinics, pain-management services, and critical care services were included in less than half of the programs that reported incentive plans. Call and late room compensation was based on varied formulas. Sixty-nine percent of academic anesthesiology departments did not vary compensation according to clinical activity during regular hours. Most did vary payments on the basis of call and/or late rooms worked. Larger departments were more likely to use clinical incentive plans.