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Biomedical subjects

J A Martyn

Publications and source records attributed to J A Martyn.

At least 73 records · Page 4Linked to original sources
PubMed1983

Competitive nonspecific binding does not explain the potentiating effects of muscle relaxant combinations.

Combination of pancuronium (Pm) with d-tubocurarine (dTC) or metocurine (mTC) produces potentiation of neuromuscular effects. We tested the hypothesis that this effect is due to decreased plasma protein and/or nonspecific (noncholinergic) tissue binding by one or the other drug such that a greater than expected proportion of unbound drug reaches its neuromuscular site of activity. By varying the concentration of Pm, dTC, and mTC, competitive binding by Pm and dTC or Pm and mTC to plasma constituents was tested in vitro by equilibrium dialysis. Drug interaction and displacement from nonspecific binding sites in tissues was tested in vivo with Pm-mTC combinations. During recovery of mTC-induced neuromuscular paralysis, monitored by evoked twitch tension, 1 mg of Pm was administered intravenously. The twitch height and plasma mTC concentrations before and after Pm administration were noted. The in vitro plasma dTC or mTC binding was not significantly altered by the addition of Pm. Similarly, plasma mTC concentrations in vivo did not increase following the administration of Pm. Thus, there was no displacement of mTC from nonspecific tissue binding sites by Pm. Our in vitro and in vivo experiments both demonstrate that there is no interaction between Pm--dTC and Pm--mTC relative to plasma or tissue binding and thus cannot explain the potentiating effect of the drug combination.

Binding, Competitive↗
PubMed1982

Pharmacokinetics of d-tubocurarine in patients with thermal injury.

d-Tubocurarine (dTc) requirements are increased following thermal injury. Significant increases in plasma binding only partially account for the altered requirement. To characterize the pharmacokinetic component of the increased requirement, the disposition of dTc was studied in eight patients with burns ranging from 15% to 80% of body surface area and compared with that in six nonburned surgical patients of comparable age and weight. Plasma levels of dTc were measured by radioimmunoassay at multiple times for 24 hours after a single bolus dose. Derived pharmacokinetic parameters were corrected for the predicted (not measured) fraction bound to plasma. The plasma disappearance curve of dTc was explained by linear sum of two or three exponential terms. The unbound central volume of distribution and renal excretion at 24 hours were significantly increased in burned patients (0.11 +/- 0.03 L/kg vs 0.057 +/- 0.015 L/kg, p less than 0.05, 57% +/- 7% vs 40% +/- 11%, p less than 0.05, respectively). On the other hand, comparable elimination half-lives (6.5 +/- 1.8 hr vs 6.2 +/- 1.3 hr, p greater than 0.05), unbound volume of distribution (0.86 +/- 0.2 L/kg vs 0.96 +/- 0.5 L/kg, p greater than 0.05), and intrinsic clearances (1.62 +/- 0.6 ml/kg/min vs 1.56 +/- 0.4 ml/kg/min, p greater than 0.05) were present in burned patients and control patients, respectively. Thus, altered kinetics contributes little to the increased doses required. Similar clearances and elimination half-lives in both groups suggest that loss of dTc through burned tissue is minimal.

Adult↗
PubMed1982

Comparative cardiovascular effects of midazolam and thiopental in healthy patients.

Midazolam, a water-soluble benzodiazepine that is shorter-acting, more potent, and less irritating to veins than diazepam, has been suggested for use for induction of anesthesia. The cardiovascular effects of an induction-sized dose (0.25 mg/kg) of midazolam in A.S.A. class I or II surgical patients (N = 11) sedated with morphine and N2O-O2 were compared in a double-blind fashion with a similar group of patients (N = 9) receiving thiopental (4.0 mg/kg). Consistent with earlier studies, patients given thiopental experienced downward trends from base line in mean arterial pressure, stroke volume, cardiac output, and heart rate; mean right atrial pressure increased slightly, whereas systemic vascular resistance did not change. Induction of anesthesia with midazolam was associated with more gradual and less pronounced hemodynamic alteration; the only significant changes from base line were decreases in mean arterial pressure 5 and 10 minutes after injection. When the two groups were compared, no significant differences were found. Midazolam is, then, as acceptable for induction of anesthesia as thiopental from a hemodynamic point of view in A.S.A. class I and II patients.

Adult↗
PubMed1981

Elevated plasma binding cannot account for the burn-related d-tubocurarine hyposensitivity.

Hyposensitivity to the nondepolarizing muscle relaxant d-tubocurarine (dTc) has been reported during the treatment of burn injury. The authors present here evidence obtained by the technique of equilibrium dialysis, that a 1.7-fold increase in dTc binding by plasma constituents occurs one to two weeks following burn injury, a timing which coincides with the onset of clinical hyposensitivity to dTc. Plasma drawn from burned patients at least one week post-burn exhibited a mean dTc-binding capacity of 5.7 +/- 0.9 nmol/g total protein compared to 3.4 +/- 0.7 nmol/g for normal plasma at a final free concentration of 0.5 microM (0.34 microgram/ml). Calculation suggests that increased plasma binding can account only for a fraction of the observed hyposensitivity; other unidentified factors must also be involved. The elevated binding capacity of plasma drawn from burned patients seems unrelated to any of the quantitative or gross qualitative changes in plasma protein profile reported here. Preliminary experiments with metocurine (mTc) show directional changes similar to dTc.

Adolescent↗
PubMed1981

Persistent ionized hypocalcemia in patients during resuscitation and recovery phases of body burns.

Despite important physiological functions, the fluctuations in plasma ionized calcium concentrations [Ca++] after major thermal injury have not been defined. Measurements of [Ca++] were undertaken in 25 patients of age ranging from 6-75 years, with body surface area burns of 25-85%. Plasma total calcium [Ca], inorganic phosphorus [Pi] and magnesium [Mg++] were also followed. Urinary excretion of the same ions was quantified in nine patients for the first 6 days postburn. The control group consisted of 12 patients who had sustained a similar injury at least 16 months earlier. Significantly low [Ca++] persisted throughout the observation period, despite an average replacement of 0.2 mM/kg.day of CaCl2. The initial hypophosphatemia and hypermagnesemia tended toward normal during the latter phase of the injury. Urinary excretion of the of the cations was not significantly elevated in the first 6 days postburn. The usual reciprocal relationship between [Ca] and [pi] was not evident, and there was no correlation between [Ca++] and the size of burn. The use of McLean-Hastings nomogram poorly predicted the [Ca++] from [Ca]. Our data indicate that marked alterations in [Ca++] homeostasis occur after thermal injury. The etiology of hypocalcemia remains to be elucidated; the physiological consequences in terms of hemodynamic function deserve further study.

Adolescent↗
PubMed1981

Thermodilution right ventricular volume: a novel and better predictor of volume replacement in acute thermal injury.

Management of acutely burned patients requires intense but meticulous fluid therapy. Indicators of satisfactory resuscitation include: intravascular and arterial pressures and urine output. The usefulness of these parameters as a predictor of cardiac index (CI) has not been tested. Compared to central venous pressure, right ventricular end-diastolic volume (RVEDV) may give a closer approximation of the preload of the right ventricle. Modifying the pulmonary artery (PA) catheter and using the thermodilution technique we measured RVEDV and right ventricular ejection fraction (RVEF) as well as the classical parameters in 16 patients of mean age 39.3 years and of mean body surface area burn 75.2%. CI best correlated with RVEDV (r = 0.75). Mean PA pressure, wedge pressure, RV end-diastolic pressure, and urine output correlated poorly with CI (r = 0.36, 0.32, 0.27, and 0.26, respectively). Unlike atrial pressures the RVEDV and RVEF are unaffected by malpositioning of transducers, airway pressure, and compliance changes of the ventricle. The measurement of RVEDV is a useful clinical tool for the assessment of preload and when used in combination with RVEF may indicate the need for inotropy.

Adolescent↗
PubMed1980

Right ventricular dysfunction in acute thermal injury.

The elevated cardiac output (CO) and pulmonary artery hypertension (PAH) observed in thermal injury offers a unique opportunity to study the effects of a combined pressure-flow load on the right ventricle in previously healthy persons. Potential responses include a diminished right ventricular ejection fraction (RVEF), increased right ventricular end-diastolic volume index (RVEDVI), and augmented myocardial oxygen consumption because of increased systolic wall tension. We investigated these factors in 15 nonhypoxic patients without sepsis having 15--75% body surface area burns using flow directed catheters and the thermodilution technique. All patients increased their CO in response in fluid resuscitation, but six patients with an elevated mean pulmonary artery pressure (greater than 20 mmHG and increased pulmonary vascular resistance (greater than 1.2 mmHg/min/L) had right ventricular dysfunction as evidenced by an increase (188 +/- 15 ml/M2) in RVEDVI and a decreased (0.26 +/- 4 ml/M2) RVEF. Patients without PAH had a smaller RVEDVI (115 +/- 4 ML/M2) and larger RVEF (0.39 +/- 0.02). Patients with PAH and RV dysfunction were older, had larger body surface area burns, lower systemic diastolic artery pressures (63 +/- 4 mmHg) and higher heart rates (114 +/- 7 beats/min); RV end-diastolic pressures were minimally elevated (9.5 +/- 1.4 mmHg). The decrease in RVEF and increase in RVEDVI may limit the hemodynamic response to fluid volume replacement and survival.

Acute Disease↗
PubMed1980

Water metabolism and antidiuretic hormone (ADH) response following thermal injury.

ADH has been implicated in the development of a positive water balance in thermal injury. However, the association of plasma ADH levels to the hemodynamic response and water and electrolyte balance of early thermal injury has not been defined. Plasma ADH was measured by radioimmunoassay in 13 patients with greater than 15% body surface area burns. In three patients frequent hemodynamic measurements were also made. Large individual variations of ADH were noted, but in general the ADH levels peaked early in the postburn period and declined thereafter. The highest mean ADH value was on day 2 (53.8 = 27 pg/ml); the lowest value on day 7 (13.4 +/- 8 pg/ml). Urine electrolytes demonstrated wide variation (Na+, 2 to 236 mEq/L; K+, 2 to 228 mEq/L) as did serum (261--331 mOsm/kg) and urine (557--785 mOsm/kg) osmolalities. No correlation was noted between ADH levels and osmolalities or hemodynamic variables. These data suggest that ADH response following burns is a stress response producing levels beyond the physiologic range for an antidiuretic effect and that the osmolar, hypovolemic, and hypotensive feedback loops are not involved: ADH seems to act as a vasoconstrictor and to have no significant effect on quality or quantity of urine. We conclude that the positive water balance following burns is not ADH mediated.

Adult↗
PubMed1979

Extrapulmonary factors influencing the ratio of arterial oxygen tension to inspired oxygen concentration in burn patients.

The ratio of arterial oxygen tension to inspired oxygen concentration (PaO2/FIO2) as an index of respiratory function was evaluated in 22 patients with body surface area burns of 15--80%. These results indicate that this ratio is limited in its applicability because extrapulmonary factors, such as cardiac output, oxygen consumption, and arterial oxygen content, can affect this index by alterations in the amount of venous desaturation. Useful estimates of intrapulmonary right to left shunt (Qs/Qt) from PaO2/FIO2 were obtained only when arteriovenous oxygen content differences (avDO2) were between 3--5 ml/dl. There were avDO2 values above and below 3--5 ml/dl in at least 35% of the observations. Under these circumstances, PaO2/FIO2 did not correctly reflect changes in Qs/Qt. Blood gases from central venous catheters did not mirror changes in true mixed venous blood and, thus, can lead to erroneous estimations of Qs/Qt. Rational therapy of reduced arterial oxygen saturation requires measurement of both extra- and intrapulmonary factors contributing to arterial desaturation. Measurement of PaO2/FIO2 alone will not estimate these factors.

Adolescent↗
PubMed1978

Pulmonary artery catheterization and thermodilution cardiac output determination in the management of critically burned patients.

Pulmonary artery catheterization was performed in thirty-nine critically burned patients. Hemodynamic changes, induced by thermal injury and its therapy, were measured. Pulmonary wedge pressure was found to be a more reliable indicator of circulating volume, whereas central venous pressure was often misleading. Measurements of both pulmonary hemodynamics and cardiac output were necessary to manage patients requiring high levels of pulmonary end-expiratory pressure (PEEP). These measurements enable one to define optimum PEEP levels which provide maximum oxygen delivery to the tissues. Depressed myocardial function was seen in the early phase of the injury. In this period dopamine administration increased left ventricular stroke work index with minimal changes in filling pressures. The usefulness of dopamine in treating this early myocardial depression deserves further study. Catheter-related complications were minimal when the catheters were used for periods of three days or less.

Adolescent↗
PubMedDate not supplied

Diaphragm acetylcholinesterase multimeric forms in mice in response to burn trauma.

This report continues our investigations concerning relative changes in acetylcholinesterase (AChE) activity in response to burn trauma. This experiment was performed in mouse diaphragm. AChE is fundamental to the operating efficiency of the neuromuscular junction. It is through such junctions that all skeletal muscle contraction occurs. This paper tests the hypothesis that burn trauma induces changes in diaphragm AChE with respect to total content, specific molecular forms, and relationships of the polymorphic forms to each other. After mice were exposed to increasing size of body surface area (20%, 30%, and 50%) diaphragms were excised at 3 weeks after burn injury. AChE activity was measured by differential extraction and velocity sedimentation on sucrose gradients. In the sham-treated control groups most of the AChE activity consisted entirely (92%) of the globular forms (S1 and S2). Asymmetric (S3 and S4) and nonextractable (H5) forms made up 2% and 6% of the AChE activity, respectively. In the burn groups all total globular activity was decreased by 1/6 to 1/3 of control groups. For these groups the asymmetric forms (S3 and S4) were increased ninefold to fourteenfold. Nonextractable forms (S5) among the groups were not different. Individual soluble globular forms (S1: 4S, 6.5S, 10S) were reduced by 50% for only the 20% and 30% BSA groups. Residual globular forms (S2) were increased threefold to ninefold. Some of the asymmetric forms (S3: 4S, 10S, 12S, and 16S) were increased fivefold to eightfold among the burn groups. Residual asymmetric (S4) and nonextractable (S5) forms were not different. This report shows that in response to burn trauma the AChE activity of the diaphragm and the interdependence of the polymorphic forms were changed at the chronic postburn period. These findings may aid in understanding the adaptive response of diaphragmatic preservation in burn trauma.

Acetylcholinesterase↗
PubMedDate not supplied

Acetylcholine receptor subunit mRNA changes in burns are different from those seen after denervation: the 1993 Lindberg Award.

Neuromuscular dysfunction of burn trauma is evidenced as muscle weakness and altered sensitivity to neuromuscular relaxants. A biochemical characteristic of the neuromuscular dysfunction is the proliferation and spread of acetylcholine receptors (AChR) throughout the skeletal muscle membrane. Depending on whether the neuromuscular dysfunction is presynaptic, synaptic, or postsynaptic in origin, the transcripts that induce the proliferation of AChR differ. This study, by quantitation of mRNA transcripts of AChR in muscle, attempts to characterize the cause of the neuromuscular dysfunction of burn trauma. Examination of the levels of mRNA encoding alpha, beta, epsilon, gamma, and delta subunits of AChR with northern blot analysis indicate significant (p < 0.03) elevations of beta-subunit mRNA with a trend for increased levels of alpha and delta transcripts. An increase of gamma-subunit mRNA, typical of presynaptic or nerve-mediated neuromuscular dysfunction, was not observed after burns. That neuronal (presynaptic) factors do not cause the neuromuscular dysfunction was confirmed by the lack of elevation of transcripts of myoD and myogenin, which also increase in "denervation states." These findings indicate that the neuromuscular dysfunction of burn trauma is most likely related to synaptic or postsynaptic factors. Further characterization of the cause of the synaptic and postsynaptic neuromuscular changes in burns will have implications for the choice of therapeutic agents to rectify the neuromuscular dysfunction.

Animals↗