Avoidance of Profound Hypothermia During Initial Reperfusion Improves the Functional Recovery of Hearts Donated After Circulatory Death.

The resuscitation of hearts donated after circulatory death (DCD) is gaining widespread interest; however, the method of initial reperfusion (IR) that optimizes functional recovery has not been elucidated. We sought to determine the impact of IR temperature on the recovery of myocardial function during ex vivo heart perfusion (EVHP). Eighteen pigs were anesthetized, mechanical ventilation was discontinued, and cardiac arrest ensued. A 15-min standoff period was observed and then hearts were reperfused for 3 min at three different temperatures (5°C; N = 6, 25°C; N = 5, and 35°C; N = 7) with a normokalemic adenosine-lidocaine crystalloid cardioplegia. Hearts then underwent normothermic EVHP for 6 h during which time myocardial function was assessed in a working mode. We found that IR coronary blood flow differed among treatment groups (5°C = 483 ± 53, 25°C = 722 ± 60, 35°C = 906 ± 36 mL/min, p < 0.01). During subsequent EVHP, less myocardial injury (troponin I: 5°C = 91 ± 6, 25°C = 64 ± 16, 35°C = 57 ± 7 pg/mL/g, p = 0.04) and greater preservation of endothelial cell integrity (electron microscopy injury score: 5°C = 3.2 ± 0.5, 25°C = 1.8 ± 0.2, 35°C = 1.7 ± 0.3, p = 0.01) were evident in hearts initially reperfused at warmer temperatures. IR under profoundly hypothermic conditions impaired the recovery of myocardial function (cardiac index: 5°C = 3.9 ± 0.8, 25°C = 6.2 ± 0.4, 35°C = 6.5 ± 0.6 mL/minute/g, p = 0.03) during EVHP. We conclude that the avoidance of profound hypothermia during IR minimizes injury and improves the functional recovery of DCD hearts.

Physiologic Changes in the Heart Following Cessation of Mechanical Ventilation in a Porcine Model of Donation After Circulatory Death: Implications for Cardiac Transplantation.

Hearts donated following circulatory death (DCD) may represent an additional source of organs for transplantation; however, the impact of donor extubation on the DCD heart has not been well characterized. We sought to describe the physiologic changes that occur following withdrawal of life-sustaining therapy (WLST) in a porcine model of DCD. Physiologic changes were monitored continuously for 20 min following WLST. Ventricular pressure, volume, and function were recorded using a conductance catheter placed into the right (N = 8) and left (N = 8) ventricles, and using magnetic resonance imaging (MRI, N = 3). Hypoxic pulmonary vasoconstriction occurred following WLST, and was associated with distension of the right ventricle (RV) and reduced cardiac output. A 120-fold increase in epinephrine was subsequently observed that produced a transient hyperdynamic phase; however, progressive RV distension developed during this time. Circulatory arrest occurred 7.6±0.3 min following WLST, at which time MRI demonstrated an 18±7% increase in RV volume and a 12±9% decrease in left ventricular volume compared to baseline. We conclude that hypoxic pulmonary vasoconstriction and a profound catecholamine surge occur following WLST that result in distension of the RV. These changes have important implications on the resuscitation, preservation, and evaluation of DCD hearts prior to transplantation.

Perioperative management of the vulnerable and failing right ventricle.

Under recognition combined with suboptimal management of right ventricular (RV) dysfunction and failure is associated with significant perioperative morbidity and mortality. The contemporary perioperative team must be prepared with an approach for early recognition and prompt treatment. In this review, a consensus-proposed scoring system is described to provide a pragmatic approach for expeditious decision-making for these complex patients with a vulnerable RV. Importantly, this proposed scoring system incorporates the context of the planned surgical intervention. Further, as the operating room (OR) represents a unique environment where patients are susceptible to numerous insults, a practical approach to anesthetic management and monitoring both in the OR and in the intensive care unit is detailed. Lastly, an escalating approach to the management of RV failure and options for mechanical circulatory support is provided.

Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.

Cardiac transplantation is in decline, in contrast to other solid organs where the number of solid organ transplants from donors after circulatory death (DCD) is increasing. Hearts from DCD donors are not currently utilized due to concerns that they may suffer irreversible cardiac injury with resultant poor graft function. Using a large animal model, we tested the hypothesis that hearts from DCD donors would be suitable for transplantation. Donor pigs were subjected to hypoxic cardiac arrest (DCD) followed by 15 min of warm ischemia and resuscitation on cardiopulmonary bypass, or brainstem death (BSD) via intracerebral balloon inflation. Cardiac function was assessed through load-independent measures and magnetic resonance imaging and spectroscopy. After resuscitation, DCD hearts had near normal contractility, although stroke volume was reduced, comparable to BSD hearts. DCD hearts had a significant decline in phosphocreatine and increase in inorganic phosphate during the hypoxic period, with a return to baseline levels after reperfusion. After transplantation, cardiac function was comparable between BSD and DCD groups. Therefore, in a large animal model, the DCD heart maintains viability and recovers function similar to that of the BSD heart and may be suitable for clinical transplantation. Further study is warranted on optimal reperfusion strategies.

Patients With a Prolonged Intensive Care Unit Length of Stay Have Decreased Health-Related Quality of Life After Cardiac Surgery.

Cardiac surgery patients with a prolonged ICU length of stay (prICULOS) have lower rates of functional survival following their procedure, however detailed information on their health related quality of life (HRQoL) is lacking. We sought to investigate the potential need for intervention in these high-risk patients through comprehensive HRQoL assessments in the months to year following their surgery. A prospective, observational pilot study was undertaken and cardiac surgery patients with a prICULOS (ICU length of stay of ≥5 days) were recruited. A control group was obtained through recruitment of cardiac surgery patients with an ICU length of stay of <5 days. In-person clinical or telephone survey HRQoL assessments were completed at 3-6 months and 1-year time points after their procedure. The standardized mean difference (SMD) was calculated for all study variable comparisons to quantify the standardized effect size observed between non-prICULOS and prICULOS patients. 789 cardiac procedures were performed during the study period and 89 patients experienced a prICULOS (10.7%). Of these 89 patients, 35 prICULOS patients were recruited along with 35 controls. 29 out of 35 prICULOS patients completed the study (83%). At the 3-6 month follow up the prICULOS patients had higher levels of weight loss, fear of falling, and driving deficits. At 1-year, prICULOS patients had persistent difficulties with activities of daily living and required more family and external support. This study demonstrates the need for closer follow up and intervention for cardiac surgery patients with a prICULOS who were found to have poorer mid and long-term HRQoL.

Transmyocardial laser revascularization remodels the intrinsic cardiac nervous system in a chronic setting.

BACKGROUND: Prospective trials have demonstrated that transmyocardial laser revascularization (TMLR) imparts symptomatic relief to patients with refractory angina. Because peak clinical effectiveness of TMLR is usually delayed by several months, it has been proposed that ventricular denervation is one mechanism whereby TMLR imparts symptomatic relief. We have demonstrated that TMLR does not denervate the heart in the acute setting, nor does it modify the intrinsic cardiac nervous system (ICNS) in the acute setting. However, the long-term effects of TMLR on the ICNS remain unknown. METHODS AND RESULTS: A holmium:yttrium-aluminum-garnet laser created 20 channels through the anterolateral left ventricular free wall of 10 dogs. Four weeks later, the function of cardiac sensory inputs to the ICNS was studied by applying veratridine (7.5 micromol/L) to ventricular sensory fields. Chronotropic and inotropic responses elicited by cardiac sympathetic or parasympathetic efferent neurons stimulated electrically (10 Hz, 4 V, 4 ms) or chemically (nicotine 5 to 20 microgram/kg IV) were also assessed. Chemical activation of epicardial sensory neurites with veratridine elicited expected ICNS excitatory responses. Electrical stimulation of sympathetic and parasympathetic efferent neurons induced expected altered cardiac responses. In contrast, the responsiveness of the ICNS to systemically administered nicotine was obtunded. CONCLUSIONS: Although chronic TMLR does not affect cardiac afferent or extracardiac efferent neuronal function, it does "remodel" the ICNS so that its responsiveness to a known potent chemical agonist (ie, nicotine) becomes obtunded. Remodeling of the ICNS may account in part for the delayed symptomatic relief that TMLR imparts to patients with refractory angina.

Skeletal muscle MAO activity in the major psychoses. Relationship with platelet and plasma MAO activities.

The skeletal muscle MAO activity of schizophrenics and patients with bipolar and unipolar affective psychoses was lower than that of normal controls. Both platelet and plasma MAO activity was significantly lower in the schizophrenics and patients with undiagnosed psychoses than in the normal controls. Platelet and plasma MAO activities were not correlated with skeletal muscle MAO activity. Both human platelet and skeletal muscle MAO are type B MAO and have similar kinetic constants. The decrease in skeletal muscle MAO activity in various types of psychotic patients is consistent with previous suggestions based on platelet studies that low MAO activity may be a nonspecific factor contributing to the development of different forms of psychopathology. Since total skeletal muscle MAO activity is the largest source of MAO in the body, it is possible that the decrease in muscle MAO activity may lead to excessive quantities of biogenic amines that could adversely affect neural activity.

Serotonin uptake in blood platelets of psychiatric patients.

Platelet serotonin (5-HT) uptake was determined in 72 newly admitted, unmedicated psychiatric patients. Decreased maximum velocity (Vmax) of 5-HT uptake was present in unipolar and bipolar depressed patients as well as schizoaffective depressed patients. The apparent Michaelis constant (km) of 5-HT uptake was normal in these groups, as was Vmax and Km in manic-depressive and chronic schizophrenic patients. Treatment of depressed patients with notriptyline hydrochloride or imipramine hydrochloride increased Km significantly. There was a trend for the increase in Km in the nortriptyline-treated patients to correlate with clinical improvement. Decreased 5-HT uptake in platelets provides additional evidence for the role of 5-HT in the pathophysiologic process of some forms of depression.

Effect of desipramine treatment on 3H-imipramine binding in the blood platelets of depressed patients.

Platelet imipramine binding (IB) was studied in depressed patients before and after treatment with desipramine for 17-28 days. Administration of desipramine was associated with a significant increase in Bmax. There was a trend for an increase in Kd, but it did not reach statistical significance. The net result of the changes in Bmax and Kd was an increase in IB. There were significant correlations between the change in depression ratings and pretreatment Kd, as well as the change in Kd during treatment. These results suggest that decreased IB is not a trait-dependent marker, but a state-dependent marker for depression.

Imipramine binding in subpopulations of normal human blood platelets.

Imipramine binding was studied in platelet membranes isolated with different proportions of heavy (young) and light (old) platelets. The Bmax, a measure of the number of binding sites, was greater in the heavier platelets than in the light platelets. However, the dissociation constant Kd (a reflection of the affinity of imipramine binding) was greater in the lighter platelets compared to the heavy platelets. These results indicate that differences in Kd and Bmax in particular membrane preparation, could be due to the differences in the relative proportion of heavy and light platelets.

Seasonal variation of imipramine binding in the blood platelets of normal controls and depressed patients.

Imipramine binding (IB) was studied in the blood platelets from normal controls and depressed patients over a 4-year period (1981-1984) to determine if seasonal variation was present in Bmax or KD. Bimonthly variation in the Bmax of IB was found in normal controls studied longitudinally. No such variation was found when individual values from normal controls were examined on a monthly or seasonal basis. Bmax in depressed patients showed a significant seasonal, but not monthly, variation. KD of IB varied in normal controls using monthly or seasonal data, but not in the probably more reliable bimonthly data. These results suggest that IB studies comparing groups of subjects should match groups for season of the year or, for greater accuracy, month of the year.

Serotonin uptake in subpopulations of normal human blood platelets.

Serotonin uptake was studied in platelet-rich plasma with different proportions of heavy (young) and light (old) platelets. The maximum velocity of serotonin uptake, a measure of the number of uptake sites (Vmax), was greater in the heavy platelets than in the light platelets. However, the uptake sites in the lighter platelets had an increased affinity (Km) for serotonin compared to the heavy platelets, which could compensate for the decreased number of uptake sites. These results indicate differences in Vmax of 5-HT uptake in particular populations could be due to differences in the relative proportions of heavy and light platelets.

Laterality and 3H-imipramine binding: studies in the frontal cortex of normal controls and suicide victims.

Serotonin [5-hydroxytryptamine (5-HT)]-sensitive imipramine binding (IB) was determined in the left and right hemisphere of frontal cortex of suicide victims and nonpsychiatric controls who died due to myocardial infarction or accident. The Kd (an inverse measure of affinity of 3H-imipramine to its binding sites) was significantly higher in left hemisphere than right hemisphere in normal controls. There were no differences in Bmax and Kd or Bmax between left hemisphere and right hemisphere in normals and suicides, respectively. These results do not support the finding of hemispheric asymmetry of 5-HT uptake as measured by IB (Bmax) in postmortem tissue from controls and suicide victims.

Effect of protein concentration on kinetic constants (Kd and Bmax) of 3H-imipramine binding in blood platelets.

3H-imipramine binding was studied in the blood platelets of 80 normal controls and 50 depressed (psychotic and nonpsychotic) patients. Protein concentration in the incubation mixture, and Kd and Bmax values were correlated in normal controls and depressed patients. A small but significant correlation between protein in the incubation mixture and Bmax was observed in normal controls and depressed patients. There was also a significant correlation between protein and Kd of imipramine binding in the blood platelets of unipolar psychotic depressed patients. However, analysis of covariance to remove the effect of protein on Kd and Bmax did not change the basic finding of decreased Bmax in the blood platelets of psychotic depressed patients.

Seasonal variation of serotonin uptake in normal controls and depressed patients.

Serotonin (5-HT) uptake in blood platelets from depressed patients and normal controls were studied over a 2-year period to determine if seasonal variations were present. Vmax, a measure of the number of 5-HT uptake sites in normal controls and depressed patients, was significantly higher in fall and winter than in spring and summer; Vmax in the depressed patients was lower than in normal controls throughout the year. Normal controls showed lower Vmax in April and June. A similar trend was present in the depressed patients but the lowest values were found in the month of December. The necessity of considering seasonal variations in this and other putative biological markers is emphasized.

Platelet monoamine oxidase. I: Effect of temperature, anticoagulant, and centrifugation technique.

Platelet yield and monoamine oxidase (MAO) activity per platelet in platelets obtained by the method of Corash, which isolates essentially all platelets from whole blood, and by a single differential centrifugation of whole blood, were compared. Platelets recovered by one spin in a swinging bucket rotor appeared to be a homogeneous population containing a reliable representation of the platelet population obtained by the Corash method since the MAO specific activity yielded by the two methods was not significantly different. The effect of the anticoagulant, temperature, and type of rotor on platelet recovery from blood and MAO activity/platelet were also studied. The MAO and plasma amine oxidaze (PAO) activities obtained from blood anticoagulated with ethylenediaminetetracetate (EDTA) were significantly greater than those found when acid-citrate-dextrose was the anticoagulant. Blood centrifuged in a swinging bucket rotor at room temperature yielded 80-90% of total platelets as compared to the 45-65% recovered with a fixed-angle rotor at 0-4 C. The most efficient method of platelet isolation was found to be a 2 1/2-min room-temperature spin at 600 X g with a swinging bucket rotor using EDTA as anticoagulant.

Serotonin uptake and imipramine binding in the blood platelets of obsessive-compulsive disorder patients.

14C-Serotonin (5-HT) uptake and 3H-imipramine binding (IB) were studied in the blood platelets of 20 obsessive-compulsive disorder (OCD) patients, 53 normal controls (5-HT uptake) and 32 normal controls (IB binding). The maximum number of binding sites (Bmax) was significantly decreased in OCD patients compared to normal controls, but there was no difference in the affinity for 3H-imipramine (Kd). The affinity for 5-HT uptake (Km) was also decreased in the OCD patients but the maximum velocity of 5-HT uptake sites (Vmax) was not significantly different in OCD patients and normal volunteers. There were trends for the Slowness Subscale of the Maudsley Obsessional-Compulsive Inventory (MOCI) to be positively correlated with the Km of 5-HT uptake (p = 0.094), whereas the Global Scale, Checking Subscale, and Doubting Conscientiousness Subscale of MOCI were negatively correlated with the Kd of IB (p = 0.066, p = 0.08, and p = 0.062, respectively). The results provide further evidence for the dysfunction of the serotonergic system in OCD.

Serotonergic measures in suicide brain: the concentration of 5-HIAA, HVA, and tryptophan in frontal cortex of suicide victims.

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and tryptophan (TRP) were determined in the frontal cortex of individuals who died by suicide, homicide, accident, or the result of physical diseases. Females had significantly higher tryptophan concentrations than males. There was a significant correlation HVA and the interval between death to refrigeration of the body. Mean HVA levels were higher from noon to 5 PM. Suicide and homicide victims had significantly higher cortical HVA concentrations than those who died of physical disease but not accident victims. This was not accounted for by gender, age, postmortem interval from death to refrigeration of the body or to autopsy, specimen storage time, or drug effects. The ratio of HVA/5-HIAA was also significantly higher in suicides compared with those who died of physical disease. No differences in cortical 5-HIAA or tryptophan concentrations between the four groups were found. There were no differences in the levels of the three substances in violent and nonviolent suicides. There were no significant correlations between 5-HIAA, HVA and TRP concentrations in all subjects or any of the four subgroups. The implications of these findings for the role of serotonin and dopamine in suicide and violence are discussed.

Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects.

The authors determined serotonin2 (5-HT2) binding in the frontal cortex of 32 suicide victims and 37 subjects who died from nonpsychiatric causes. The maximum number of binding sites (Bmax) and the affinity (Kd) were significantly higher in subjects who had committed suicide than in control subjects. However, there was no difference in Kd between these two groups after the influence of age, race, sex, and postmortem delay was covaried. The Bmax of subjects who had committed violent suicide was significantly greater than that of control subjects.

Effect of neuroleptic drugs on platelet monoamine oxidase in psychiatric patients.

The authors determined the platelet MAO activity of 57 psychotic patients after a placebo period and after 3-65 days of neuroleptic treatment. Platelet MAO activity significantly decreased in both men and women after neuroleptic treatment. The platelet MAO activity of neuroleptic-treated schizophrenic women was significantly less than that of drug-free schizophrenic women, who did not differ from normal women. There were trends in the same direction for the schizophrenic men. Previous studies that reported lower platelet MAO activity in neuroleptic-treated schizophrenic patients than in normal controls may have been influenced by this neuroleptic effect.