Reversible myocardial depression after massive catecholamine release from a pheochromocytoma.
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Adrenal Gland Neoplasms↗
Biomedical subjects
M M Parker
Publications and source records attributed to M M Parker.
Repair and mutagenesis of the genome of a deletion mutant of the coronavirus mouse hepatitis virus by targeted RNA recombination.
The genetic characterization of a nucleocapsid (N) protein mutant of the coronavirus mouse hepatitis virus (MHV) is described. The mutant, Albany 4 (Alb4), is both temperature sensitive and thermolabile. Analysis of the progeny of a mixed infection showed that the defective Alb4 allele is recessive to wild type, and its gene product is diffusible. The N protein of Alb4 was found to be smaller than its wild-type counterpart, and sequence analysis of the Alb4 N gene revealed that it contains an internal deletion of 87 nucleotides, producing an in-frame deletion of 29 amino acids. All of these properties of Alb4 made it ideal for use as a recipient in a targeted RNA recombination experiment in which the deletion in Alb4 was repaired by recombination with synthetic RNA7, the smallest MHV subgenomic mRNA. Progeny from a cotransfection of Alb4 genomic RNA and synthetic RNA7 were selected for thermal stability. Polymerase chain reaction analysis of candidate recombinants showed that they had regained the material that is deleted in the Alb4 mutant. They also had acquired a five-nucleotide insertion in the 3' untranslated region, which had been incorporated into the synthetic RNA7 as a molecular tag. The presence of the tag was directly verified, as well, by sequencing the genomic RNA of purified recombinant viruses. This provided a clear genetic proof that the Alb4 phenotype was due to the observed deletion in the N gene. In addition, these results demonstrated that it is possible to obtain stable, independently replicating progeny from recombination between coronavirus genomic RNA and a tailored, synthetic RNA species.
Amino Acid Sequence↗
Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin.
Endotoxin is a major mediator of the life-threatening cardiovascular dysfunction that characterizes Gram-negative sepsis. In animal models of endotoxemia, pretreatment with ibuprofen or pentoxifylline attenuates some of these cardiovascular changes. To evaluate the effects of these agents on the human cardiovascular response to endotoxemia, hemodynamic variables were measured serially in 24 normal subjects who were given intravenous endotoxin. The subjects were randomized to receive oral ibuprofen (n = 9), pentoxifylline (n = 10), or no medication before endotoxin administration (n = 5). The subjects were volume loaded 3-5 h after endotoxin administration, and hemodynamic measurements were reassessed. Core temperature after endotoxin alone or endotoxin-pentoxifylline approached a maximum at 3 h (greater than or equal to 38.6 degrees C), while the endotoxin-ibuprofen group remained afebrile. At 3 and 5 h, all three groups had significant increases in heart rate, cardiac index, oxygen delivery, and oxygen consumption, while systemic vascular resistance index decreased significantly from baseline. The oxygen extraction ratio remained unchanged. After volume loading, the left ventricular ejection fraction and left ventricular end-diastolic and end-systolic volume indexes did not differ among the groups. The hyperdynamic cardiovascular response to endotoxin in humans occurs in the absence of fever and is not significantly ameliorated by oral cyclooxygenase or phosphodiesterase inhibition.
Adult↗
Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy.
Septic shock is the commonest cause of death in intensive care units. Although sepsis usually produces a low systemic vascular resistance and elevated cardiac output, strong evidence (decreased ejection fraction and reduced response to fluid administration) suggests that the ventricular myocardium is depressed and the ventricle dilated. In survivors, these abnormalities are reversible. Failure to develop ventricular dilatation in nonsurvivors suggests that dilatation is a compensatory mechanism needed to maintain adequate cardiac output. With a canine model of septic shock that is very similar to human sepsis, myocardial depression was confirmed using load-independent measures of ventricular performance. Endotoxin administration to humans simulates the qualitative, cardiovascular abnormalities of sepsis. The pathogenesis of septic shock is extraordinarily complex. Diverse microorganisms can generate toxins, stimulating release of potent mediators that act on vasculature and myocardium. A circulating myocardial depressant substance has been closely associated with the myocardial depression of human septic shock. Therapy has emphasized early use of antibiotics, critical care monitoring, aggressive volume resuscitation, and, if shock continues, use of inotropic agents and vasopressors. Pharmacologic or immunologic antagonism of endotoxin or other mediators may prove to enhance survival in this highly lethal syndrome.
Animals↗
Structure and function studies of the nucleocapsid protein of mouse hepatitis virus.
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Animals↗
Sequence comparison of the N genes of five strains of the coronavirus mouse hepatitis virus suggests a three domain structure for the nucleocapsid protein.
To obtain information about the structure and evolution of the nucleocapsid (N) protein of the coronavirus mouse hepatitis virus (MHV), we determined the entire nucleotide sequences of the N genes of MHV-A59, MHV-3, MHV-S, and MHV-1 from cDNA clones. At the nucleotide level, the N gene sequences of these viral strains, and that of MHV-JHM, were more than 92% conserved overall. Even higher nucleotide sequence identity was found in the 3' untranslated regions (3' UTRs) of the five strains, which may reflect the role of the 3' UTR in negative-strand RNA synthesis. All five N genes were found to encode markedly basic proteins of 454 or 455 residues having at least 94% sequence identity in pairwise comparisons. However, amino acid sequence divergences were found to be clustered in two short segments of N, putative spacer regions that, together, constituted only 11% of the molecule. Thus, the data suggest that the MHV N protein is composed of three highly conserved structural domains connected to each other by regions that have much less constraint on their amino acid sequences. The first two conserved domains contain most of the excess of basic amino acid residues; by contrast, the carboxy-terminal domain is acidic. Finally, we noted that four of the five N genes contain an internal open reading frame that potentially encodes a protein of 207 amino acids having a large proportion of basic and hydrophobic residues.
Amino Acid Sequence↗
Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans.
Septic shock in humans is usually characterized by a high cardiac output, a low systemic vascular resistance, reversible depression of left ventricular ejection fraction, and transient left ventricular dilatation. The relationship of left ventricular to right ventricular function in septic shock is poorly understood. To evaluate right ventricular vs left ventricular performance and to evaluate the relation of biventricular performance to survival, we performed serial hemodynamic and radionuclide angiographic studies in 39 patients with septic shock. Right ventricular ejection fraction was calculated using the two regions of interest method. There were 22 survivors and 17 nonsurvivors. Comparing initial with final (after recovery for survivors; within 24 hours of death for nonsurvivors) studies, each survivor's cardiovascular performance returned toward normal, with significant increases in mean arterial pressure, left and right ventricular ejection fraction, and right ventricular stroke work index. Their profiles also demonstrated significant decreases in central venous pressure, pulmonary artery wedge pressure, pulmonary artery mean pressure, and left and right ventricular end-diastolic volume indices. From initial to final study in the nonsurvivors, there was a statistically significant increase in heart rate but no change in any other cardiovascular parameter, indicating a persistence of the initial cardiovascular dysfunction until death. Comparing serial studies, the pattern of change in right vs left ventricular function was very similar (same direction in 82 percent of patients). Thus, myocardial depression in human septic shock affects both ventricles simultaneously with a similar pattern of dysfunction.
Adolescent↗
Ultrasound guidance improves the success rate of internal jugular vein cannulation. A prospective, randomized trial.
STUDY OBJECTIVE: To compare conventional versus ultrasound-guided internal jugular vein cannulation techniques. DESIGN: Patients were randomly assigned to receive either conventional or two-dimensional ultrasound-guided internal jugular vein cannulation. Patients who could not be cannulated with five or fewer passes by either technique, were crossed over to the other technique. SETTING: Clinical research unit in a tertiary care center. PATIENTS: All consecutive patients who required urgent or urgent-elective internal jugular vein cannulation during the study period. INTERVENTIONS: The two-dimensional ultrasound transducer imaged all cannulation attempts. For patients randomized to ultrasound guidance, the operator viewed two-dimensional ultrasound images, and received verbal guidance from the ultrasound technician. For patients randomized to the conventional arm, two-dimensional ultrasound images were recorded without visual or verbal feedback. MEASUREMENTS AND MAIN RESULTS: Two-dimensional ultrasound was significantly better than conventional guidance in reducing the number of failed site cannulations from 6/17 (35 percent), to 0/12 (0 percent), p less than 0.05. Two-dimensional ultrasound also reduced the mean number of passes required to cannulate the vein from 3.12 to 1.75 (p less than .05), and was also successful in six/six (100) of patients who failed cannulation by conventional means (p less than 0.05). CONCLUSIONS: Intensivists can increase successful internal jugular vein cannulation using ultrasound guidance. Two-dimensional ultrasound should be considered for patients difficult to cannulate or those at high risk of cannulation complications.
Catheterization, Central Venous↗
A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy.
Although prednisone has been used to treat patients with idiopathic dilated cardiomyopathy, its efficacy has not been rigorously studied. We therefore randomly assigned 102 patients to either treatment with prednisone (60 mg per day) or a control group. At three months, improvement, defined prospectively as an increase in the ejection fraction of greater than or equal to 5 percentage points, was observed in 53 percent of the patients receiving prednisone and 27 percent of the controls (P = 0.005). The mean (+/- SE) ejection fraction increased 4.3 +/- 1.5 percentage points (from 17.9 +/- 1.0 to 22.2 +/- 1.6 percent) in the prednisone group, as compared with 2.1 +/- 0.8 percentage points (from 17.1 +/- 1.1 to 19.3 +/- 1.4 percent) in the control group (P = 0.054). All patients were categorized prospectively in two separately randomized subgroups. "Reactive" patients (n = 60) were those who had fibroblastic (n = 36) or lymphocytic (n = 2) infiltration or immunoglobulin deposition (n = 16) on endomyocardial biopsy, a positive gallium scan (n = 7), or an elevated erythrocyte sedimentation rate (n = 18). "Nonreactive" patients (n = 42) had none of these features. At three months, 67 percent of the reactive patients who received prednisone had improvement, as compared with 28 percent of the reactive controls (P = 0.004). Nonreactive patients did not improve significantly with prednisone (P = 0.51). After three months, reactive patients who received prednisone daily were switched to alternate-day therapy (60 mg every other day), and after six months the improvement seen earlier was no longer present. These data suggest that patients with idiopathic dilated cardiomyopathy may have some improvement when given a high dose of prednisone daily. However, the increases in the ejection fraction that we observed during prednisone treatment were small, their duration was limited, and the side effects were important. Overall, prednisone was judged to have only marginal clinical benefit, and should not be administered as standard therapy for dilated cardiomyopathy.
Cardiomyopathy, Dilated↗
The cardiovascular response of normal humans to the administration of endotoxin.
Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.
Adult↗
A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock.
Using spontaneously beating rat myocardial cells as an in vitro model of myocardial depression, recent studies demonstrated that septic shock patients' sera frequently contain a myocardial depressant substance (MDS) that is associated with a reversible decrease in left ventricular ejection fraction (LVEF). To further characterize MDS, 50 consecutive patients with possible septic shock were studied serially from shock onset until recovery or death. Thirty-four patients had criteria diagnostic of septic shock, and 16 had a nonseptic critical illness. Of the 34, 14 met strict criteria for circulating MDS, with a mean inhibition of 35 percent (range 20 percent to 62 percent). Compared with those patients not exhibiting significant MDS activity, the 14 MDS-positive patients had a lower mean minimal EF (28 percent vs 39 percent, p less than 0.01), a greater mean decrease in EF (22.1 percent vs 8.8 percent, p = 0.002), a higher pulmonary artery wedge pressure (16.8 vs 11.9 mm Hg, p less than 0.01), greater LV dilatation (162 vs 118 ml/m2, p = 0.02), and a higher circulating mean peak lactic acid (6.9 vs 2.7 mmol/L, p less than 0.01). In the 14 MDS-positive patients, the in vitro myocardial cell depression had a negative correlation with the in vivo EF (r = -060, p less than 0.05). These findings suggest that a circulating MDS is a cause of the myocardial depression frequently accompanying human septic shock.
Adolescent↗
Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock.
Volume infusion, to increase preload and to enhance ventricular performance, is accepted as initial management of septic shock. Recent evidence has demonstrated depressed myocardial function in human septic shock. We analyzed left ventricular performance during volume infusion using serial data from simultaneously obtained pulmonary artery catheter hemodynamic measurements and radionuclide cineangiography. Critically ill control subjects (n = 14), patients with sepsis but without shock (n = 21), and patients with septic shock (n = 21) had prevolume infusion hemodynamic measurements determined and received statistically similar volumes of fluid resulting in similar increases in pulmonary capillary wedge pressure. There was a strong trend (p = 0.004) toward less of a change in left ventricular stroke work index (LVSWI) after volume infusion in patients with sepsis and septic shock compared with control subjects. The LVSWI response after volume infusion was significantly less in patients with septic shock when compared with critically ill control subjects (p less than 0.05). These data demonstrate significantly altered ventricular performance, as measured by LVSWI, in response to volume infusion in patients with septic shock.
Critical Care↗
Interleukin-2 administration causes reversible hemodynamic changes and left ventricular dysfunction similar to those seen in septic shock.
Interleukin-2, a lymphocyte product, has well demonstrated antitumor activity in humans. Early clinical studies showed hemodynamic alterations in patients receiving the drug as antitumor immunotherapy. We serially assessed interleukin-2-associated hemodynamic parameters and left ventricular ejection fractions in five patients with neoplastic diseases unresponsive to conventional therapies. By day 4 of therapy, compared with baseline (preinterleukin-2), all patients developed tachycardia (p less than 0.01), decreased mean arterial blood pressure (p less than 0.05), increased cardiac index (p less than 0.05), and decreased systemic vascular resistance (p less than 0.01). In addition, left ventricular ejection fraction fell from 58.0 +/- 4.7 to 36.4 +/- 4.0 percent (0.05 less than p less than 0.10), which was associated with a trend toward left ventricular dilatation manifested by an increase in left ventricular end-diastolic volume index. Transient renal dysfunction was noted in all five patients, and one developed transient respiratory failure; both types of organ dysfunction recovered to baseline values after cessation of immunotherapy. Thus, interleukin-2 induces multiple reversible cardiovascular abnormalities that are similar to the hemodynamic manifestations of human septic shock.
Adult↗
Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis.
Forty-eight septic shock patients with positive blood cultures had conventional serial hemodynamic evaluations until recovery or death to identify early cardiovascular variables that predicted outcome. There were 19 (40%) survivors and 29 nonsurvivors. At the initial evaluation, both survivors and nonsurvivors demonstrated an elevated cardiac index (CI), low systemic vascular resistance index (SVRI), and normal stroke volume index. However, only an initial heart rate (HR) less than 106 beat/min significantly predicted survival. Twenty-four hours after the onset of shock, both an HR less than 95 beat/min and an SVRI greater than 1529 dyne.sec/cm5.m2 predicted survival. Comparing the hemodynamic profiles from the initial to the 24 h time point, a decrease in HR greater than 18 beat/min or a decrease in CI greater than 0.5 L/min.m2 predicted survival. Twenty-two deaths occurred in the first week of study, of which 18 (82%) were due primarily to low SVRI and four (18%) to low CI. Seven deaths occurred after 1 wk, all of which were due to multiple organ failure.
Adolescent↗
Adult respiratory distress syndrome in patients with severe neutropenia.
Most investigators believe that the pulmonary endothelial damage that is characteristic of the adult respiratory distress syndrome (ARDS) requires the action of neutrophils. In a retrospective review of patients with ARDS, we looked for cases that had developed in patients who already had neutropenia. Four clinical criteria were required for the diagnosis of ARDS: the occurrence of a precipitating event, diffuse bilateral pulmonary infiltrates on a chest x-ray film, a normal intravascular volume (as reflected by a wedge pressure of less than 18 mm Hg), and arterial hypoxemia. During 2 1/2 years, 11 patients fulfilled these clinical criteria, had severe neutropenia that antedated the onset of ARDS, and had pulmonary histologic specimens obtained during the early stages (less than seven days) of clinical respiratory distress. Five of these specimens showed diffuse alveolar damage without evidence of infectious pneumonitis (the histopathological finding characteristic of ARDS), and none had a neutrophil infiltrate. We conclude that ARDS can occur in the setting of severe neutropenia, without pulmonary neutrophil infiltration.
Adult↗
The coronary circulation in human septic shock.
Reversible myocardial depression, manifested by ventricular dilatation and decreased ejection fraction, is common in human septic shock. A proposed mechanism, based on animal studies, is myocardial ischemia resulting from inadequate coronary blood flow. Coronary flow observations have not been reported for human septic shock. To determine whether myocardial depression in human septic shock is associated with reduced coronary flow, thermodilution coronary sinus catheters were placed in seven patients with septic shock for measurements of coronary flow and myocardial metabolism. Four of the seven patients developed myocardial depression. These patients had coronary flow similar to or higher than that of control subjects and similar to that of the other three patients, who did not develop myocardial depression. None of the patients had net myocardial lactate production. In general, compared with values in control subjects, the oxygen content difference (arterial minus coronary sinus) was narrowed, and the fractional extraction of arterial oxygen was diminished. This pattern of disordered coronary autoregulation is analogous to the pattern of arteriovenous shunting in other organs in patients with septic shock. The preservation of coronary flow, the net myocardial lactate extraction, and the increased availability of oxygen to the myocardium argue against global ischemia as the cause of myocardial depression in human septic shock.
Acquired Immunodeficiency Syndrome↗
Gated blood-pool scanning in the critically ill: a valuable tool for clinical research.
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Critical Care↗
A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.
We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.
Adolescent↗