Intravenous immunoglobulin g attenuates pulmonary hypertension but induces local neutrophil influx in meconium aspiration in piglets.

BACKGROUND: Pulmonary hypertension and inflammation are well-identified pathogenetic features in meconium aspiration syndrome of newborns, but current approaches to their treatment or prevention are still often unsatisfactory. OBJECTIVES: To investigate the possible protective effects of human intravenous immunoglobulin G (IVIG) on the hypertensive and inflammatory lung injury in severe neonatal meconium aspiration. METHODS: Eleven newborn (10-12 days old) ventilated and catheterized piglets that received an intratracheal bolus (3 ml/kg) of a 65-mg/ml mixture of human meconium were studied for 6 h. IVIG was infused in 5 piglets 30 min before meconium administration, and 6 piglets served as controls and received the vehicle only. RESULTS: Meconium instillation induced a biphasic pulmonary hypertensive response, which was significantly diminished by IVIG pretreatment. Similarly, IVIG improved the oxygenation of the piglets, but the intrapulmonary shunt fraction or systemic hemodynamic parameters did not differ between the study groups, except of a minor decrease in the mean arterial blood pressure caused by IVIG. The blood leukocyte count was comparable in the 2 groups. The lung tissue ultrastructural and histological changes, number of apoptotic cells and phospholipase A2 activity were similar in the 2 groups. The amount of neutrophil accumulation, assessed by myeloperoxidase activity, was however significantly increased in macroscopically damaged lung tissue after IVIG administration. CONCLUSIONS: Our results thus indicate that IVIG treatment of newborns with severe meconium aspiration significantly diminishes the pulmonary hypertensive response and improves oxygenation, but the effects do not extend to protection of lung cellular injury.

Dexamethasone treatment attenuates pulmonary injury in piglet meconium aspiration.

To investigate the pulmonary effects of steroid treatment in neonates with meconium aspiration, 25 10- to 12-d-old piglets were studied for 6 h after an intratracheal bolus of human meconium. Dexamethasone (0.5 mg/kg) was given in two treatment schedules, either 1 h before (n = 6) or 1 h after meconium instillation (n = 8). Eight piglets served as controls. Three additional piglets were given dexamethasone without meconium instillation. Pulmonary hemodynamics and oxygenation were followed, and lung tissue samples investigated for signs of inflammation and ultrastructural injury, including apoptosis. Pulmonary artery pressure and vascular resistance increased after meconium instillation, but this rise was significantly prevented after prophylactic dexamethasone. This treatment also improved the acutely deteriorated oxygenation of the piglets after meconium insufflation. Prophylactic, but not early, dexamethasone treatment further protected the lungs from the ultrastructural changes caused by meconium instillation. Additionally, the increase of apoptotic epithelial cell deaths was significantly prevented by both dexamethasone treatments. These results show that prophylactic dexamethasone treatment significantly attenuates the early pulmonary hemodynamic deterioration and structural lung damage caused by meconium aspiration. Further studies on the apoptosis-inhibiting effect of dexamethasone administration in neonatal lungs exposed to heavy meconium are warranted.

In vivo detection of vascular adhesion protein-1 in experimental inflammation.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Nitric oxide inhalation inhibits pulmonary apoptosis but not inflammatory injury in porcine meconium aspiration.

To investigate the possible protective effects of nitric oxide (NO) inhalation in newborns with meconium aspiration, 18 10-12-d-old piglets were studied for 6h after an intratracheal bolus (3 ml/kg) of a 65-mg/ml mixture of human meconium. Twelve of the piglets were treated with continuous NO inhalation at a dose of 1 ppm (n = 6) or 10 ppm (n = 6), started 30 min before the insult. Pulmonary haemodynamics and systemic oxygenation were followed, and lung tissue samples were studied for signs of inflammation, evidence of ultrastructural injury and apoptotic cell changes. Inhalation of 10 ppm NO, in contrast to 1 ppm NO, significantly delayed the meconium-induced pulmonary pressure rise and the increase in intrapulmonary shunt fraction, and maintained better oxygenation in the piglets. Histologically and biochemically, treatment with 1 or 10 ppm NO inhalation did not protect the lungs against meconium-induced inflammatory injury. Further, ultrastructural lung tissue analysis revealed a significant amount of alveolar exudate and oedematous alveolar epithelium and endothelium after meconium instillation, also in the lungs treated with NO inhalation. However, the increase in apoptotic epithelial cell deaths, previously shown to be stimulated by intratracheal meconium, was significantly impeded after inhalation of 10 ppm. These results thus show that early continuous NO inhalation controls the rise in pulmonary artery pressure and improves the efficiency of arterial oxygenation, and further prevents the increase in epithelial apoptosis, but does not protect against early inflammatory damage caused by meconium aspiration.

Meconium aspiration induces a concentration-dependent pulmonary hypertensive response in newborn piglets.

To investigate the effects of aspirating different meconium concentrations on the pulmonary circulation in 10- to 12-day-old piglets, 30 catheterized animals were studied. The piglets received an intratracheal bolus of 3 ml/kg of a mixture of human meconium in saline with concentrations of 20 mg/ml (light, n = 7), 40 mg/ml (moderate, n = 6), or 65 mg/ml (thick, n = 10) meconium in saline. Control piglets (n = 7) received 3 ml/kg of intratracheal saline. Pulmonary and systemic pressures were measured and vascular resistances calculated at baseline and serially for 4 hours after instillation. Four of the piglets died early and were excluded from the study. In addition, 23 samples of human meconium-stained amniotic fluid were collected at delivery for determination of their meconium concentration. After an initial rise in pulmonary artery pressure and vascular resistance after meconium and saline instillation, pulmonary artery pressure and resistance increased progressively and concentration-dependently in the meconium groups, but returned to baseline in the control group. The saline and meconium-induced initial increases, and the subsequent meconium-stimulated progressive rise in vascular resistance occurred mainly in the postarterial segment. There were no significant changes in systemic hemodynamics. Mean airway pressure increased and oxygenation deteriorated after meconium instillation. The impairment of oxygenation depended on the meconium concentration in the instilled bolus and persisted throughout the study after moderate and thick meconium instillation. Similarly, the intrapulmonary shunt fraction increased initially and remained elevated in the moderate and thick meconium groups. Meconium concentrations in the human amniotic fluid samples were in the same range as concentrations used in the present experimental study. These results indicate that aspirated meconium at concentrations found in light to moderate meconium-stained human amniotic fluid has significant effects on pulmonary hemodynamic and oxygenation in newborn piglets.

Methylprednisolone attenuates the pulmonary hypertensive response in porcine meconium aspiration.

Severe neonatal aspiration of meconium is frequently complicated by fatal pulmonary hypertension. The protective effect of an i.v. bolus of methylprednisolone on meconium aspiration-induced hypertensive lung injury was studied in anesthetized pigs with adapted lung circulation. Eleven 10-wk-old pigs received 3 mL/kg 20% human meconium via the endotracheal tube. Five of them were pretreated with 30 mg/kg methylprednisolone 30 min before aspiration. Ventilator settings were adjusted to keep arterial PO2 above 8 kPa and arterial PCO2 below 5 kPa. Meconium insufflation induced a biphasic pulmonary pressor response during the 6 h follow-up. Methylprednisolone tended to prevent the early (0-1 h) increase in pulmonary artery pressure and inhibited significantly the second phase (1-6 h) progressive rise in pulmonary artery pressure and pulmonary vascular resistance. This inhibition of resistance increase was most profound in the postarterial segment of the lung circulation, as determined by pulmonary artery occlusion. Additionally, the methylprednisolone pretreated group demonstrated a significant decrease in venous admixture together with improved oxygenation during the late phase after the insult, and further showed evidence of diminished lung edema formation. Although meconium aspiration-induced fall in blood leukocyte concentration was inhibited by methylprednisolone pretreatment, no histologic difference was found in pulmonary leukocyte sequestration. Our results thus show that in adapted porcine lungs methylprednisolone pretreatment improves oxygenation and attenuates the meconium aspiration-induced pulmonary hypertensive response by preventing the increase in the postarterial resistance.

Adenosine triphosphate treatment for meconium aspiration-induced pulmonary hypertension in pigs.

To investigate the pulmonary haemodynamic effects of meconium aspiration and subsequent adenosine triphosphate (ATP) treatment, 12 anaesthetized and ventilated pigs (wt 24-28 kg) received either ATP or an equal volume of saline into the right heart in doses of 0.02 to 0.80 mumol kg-1 min-1 after intratracheal administration of 2 mL kg-1 of human meconium. Meconium instillation induced significant increases in pulmonary vascular pressures and total and postarterial resistances calculated from pulmonary artery occlusion studies, but did not affect the systemic haemodynamics, except for a fall in heart rate and increase in central venous pressure. Infusion of ATP at the lowest doses (0.02 and 0.08 mumol kg-1 min-1) selectively decreased the pulmonary arterial pressure and vascular resistance and at 0.32 and 0.80 mumol kg-1 min-1 reduced both the pulmonary and systemic resistances. In the lung circulation the increasing doses of ATP reduced preferably the arterial but also the postarterial resistance. Withdrawal of ATP infusion led to a significant rebound effect especially in the postarterial segment of the lung circulation. Meconium aspiration thus induces an acute, predominantly postarterial obstruction in the lung circulation and infusion of ATP at low doses selectively dilates the pulmonary vascular bed and may help to preclude elevation of capillary pressures in meconium aspiration-induced pulmonary hypertension.

Meconium aspiration induces ARDS-like pulmonary response in lungs of ten-week-old pigs.

To investigate whether aspiration of meconium induces a hemodynamic and histologic pulmonary response similar to that frequently seen in experimental acute respiratory distress syndrome, twelve 10-week-old pigs with postnatally adapted lungs were studied. Six 10-week-old pigs received 3 ml/kg 20% human meconium via the endotracheal tube. Six control pigs of the same age were given sterile saline. Ventilator settings were adjusted to keep PaO2 above 8 kPa and PaCO2 below 5 kPa. The pulmonary hemodynamic response to aspiration consisted of two separate hypertensive components. An initial peak in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) was followed by a progressive increase in PAP and PVR in the meconium group, whereas in the saline group these parameters returned to baseline levels. The distribution of PVR, determined by pulmonary artery occlusion, was characterized by an increase in the postarterial resistance immediately after meconium aspiration and a progressive increase in both arterial and postarterial resistance during the later phase. On histological examination, marked neutrophil sequestration was seen in the meconium lungs. In addition, lung edema formation was significantly enhanced in the meconium group, as shown by an increased lung wet/dry weight ratio. Thus, meconium aspiration resulted in a biphasic pulmonary pressor response and severe pulmonary inflammation. This response resembled that of models of experimental acute respiratory distress syndrome following diverse types of precipitating insults; this suggests that similar pathophysiologic mechanisms are elicited and cause similar pulmonary dysfunction following different forms of lung injury.

Transcephalic electrical impedance in the study of cerebral circulation in a juvenile pig model.

Transcephalic electrical impedance offers a technique for non-invasive, cot-side monitoring of neonatal cerebral circulation but the exact nature of the signal is somewhat ambiguous. The impedance signal is examined in an animal project where the ventilator settings are adjusted (20 min-1-10 min-1-40 min-1 for 10 min periods each) to produce circulatory changes. Six juvenile pigs are intubated, and ECG, arterial blood pressure, carotid flow (CF) by electromagnetic flowmeter and impedance are continuously monitored and stored on analogue tape. Cardiac output by thermodilution, blood oxygen (pO2) and carbon dioxide (pCO2) tensions are measured. ECG is converted to heart rate, mean blood pressure is integrated, and the high-frequency (1.50-4.00 Hz) component of the impedance signal delta Z is computed using autoregressive spectral estimation. Stroke volume, peripheral vascular resistance (PVR) and cerebral vascular resistance (CVR) are calculated. pCO2 and CF increase and pO2 decreases during hypoventilation. CF correlates positively with cardiac output, stroke volume, delta Z and pCO2, and negatively with pO2 and CVR. delta Z correlates positively with heart rate and cardiac output, and negatively with PVR and CVR. It is concluded that the impedance signal is related to the amount of blood transmitted to the brain by every beat of the heart, depending on the changes in both the systemic circulation and the cerebral vascular compliance.

Effects of dexmedetomidine on coronary hemodynamics and myocardial oxygen balance.

OBJECTIVE: alpha 2-adrenergic agonists decrease central sympathetic outflow and maintain normal transmural myocardial blood flow distribution, but intravenous bolus doses of these agents can also induce excessive coronary vasoconstriction and myocardial ischemia. The hypothesis of the present study was that a rapid intravenous bolus of dexmedetomidine, a specific alpha 2-adrenergic agonist, will cause coronary vasoconstriction and accompanying myocardial ischemia in young pigs. DESIGN: Prospective, controlled study on experimental animals. SETTING: Animal laboratory of a university cardiorespiratory research center. PARTICIPANTS: Twelve domestic 8-week-old open-chest pigs, anesthetized with high-dose fentanyl. Another six pigs served as controls. INTERVENTIONS: Sequential intravenous dexmedetomidine boluses of 3, 10, and 30 mg/kg were administered, and responses were measured during peak changes (2 minutes after injection) and during recovery after each dose. MEASUREMENTS AND MAIN RESULTS: Left anterior descending coronary artery blood flow, calculated regional coronary vascular resistance, myocardial extraction of oxygen and lactate, plasma catecholamine levels, and conventional central hemodynamic parameters were measured. The two higher doses of dexmedetomidine induced 21% and 29% immediate increases in left anterior descending coronary artery blood flow. At the same time mean systemic blood pressure and pulmonary capillary wedge pressure increased, and calculated regional coronary vascular resistance increased. Myocardial extraction of oxygen and lactate remained unchanged. CONCLUSIONS: Large intravenous doses of dexmedetomidine caused moderate regional coronary vasoconstriction without metabolic signs of myocardial ischemia in young domestic pigs at the same time as a marked vasoconstrictive response in the systemic circulation.

Effects of glycopyrrolate and atropine on heart rate variability.

Analysis of heart rate variability, combined with physiological tests (deep breathing and tilt tests) was used to characterise the effects of atropine and glycopyrrolate on the parasympathetic nervous tone of the heart in healthy male volunteers. The low dose of atropine (120 micrograms) administered as a continuous infusion in 15 min was associated with parasympatomimetic effects estimated by the slowing of the heart rate and an increase of the mean and beat-to-beat heart rate variability. The bradycardia and increase of heart rate variability following infusion of glycopyrrolate (50 micrograms) was less marked and did not differ significantly from that of placebo. The higher doses of atropine (720 micrograms) and glycopyrrolate (300 micrograms) administered as a continuous infusion in 15 min produced an equal vagal cardiac blockade characterised by significant tachycardia and a decrease in overall and beat-to-beat heart rate variability. It is concluded that at low doses the parasympatomimetic action of glycopyrrolate is less marked than that of atropine; and at higher doses only small differences exist between these two muscarinic antagonists in their effects on cardiac vagal outflow, assessed by heart rate and heart rate variability.

Regulation of heart rate variation by the autonomic nervous system in neonatal lambs.

We studied the role of the autonomic nervous system in the regulation of heart rate variation (HRV) in 12 chronically instrumented neonatal lambs. HRV was quantified from ECG tracings by computing periodic HRV distributions at frequencies of 0.02-1.00 Hz, using power spectral analysis of heart rate, and also by HRV indices. Heart rate declined more during the 1st than the 2nd mo after birth. Multiple regression analysis showed that the heart rate responses to vagal and to beta-adrenergic blockade had an independent negative association both with age and with the initial mean heart rate, whereas the overall HRV response had a positive association with age. Vagal blockade led to a 70-80% decrease in the beat-to-beat HRV in all lambs (p less than 0.001). The overall HRV indices decreased by 40-65% in lambs (less than 30 d old (p less than 0.001) and about 30% in those greater than 30 d old (p less than 0.05). In the power spectrum the greatest decrease was seen in the high-frequency components of HRV. beta-Blockade led to a decrease of about 50% in all HRV (p less than 0.001) in the younger lambs, without frequency selection. In the older lambs, it had no effect on the beat-to-beat HRV, but the overall HRV (coefficient of variance) decreased maximally by 40% (p less than 0.01), with a significant reduction in the low-frequency components of HRV. These results suggest that in the regulation of HRV after birth dual control via the autonomic nervous system is most important. In the older lambs, developmental changes result in precise regulation of the fast heart rate fluctuations mainly by the vagal division, whereas the slow fluctuations are partially regulated by the vagal and beta-adrenergic divisions.

Renal glucose and lactate metabolism in endotoxin shock in dogs.

Renal metabolism of glucose and lactate was studied in ten adult beagle dogs during pentobarbital anesthesia. Six dogs were submitted to hypodynamic shock by means of an intravenous bolus injection of Escherichia coli endotoxin, 0.5 mg/kg over 15 min. Four dogs received only saline solution and served as controls. Sudden cardiac depression, hypotension and moderate renal hypoperfusion were observed in the endotoxin-injected animals. Acidosis and oliguria also occurred during the 5-hour study. Arterial and renal venous glucose concentration increased transiently during the early phase of endotoxin shock. In the control group glucose levels increased slightly by the end of the experiment. Despite marked hyperlactatemia in the endotoxin group, the arteriovenous lactate difference remained almost unchanged. Renal uptake of lactate and output of glucose were not influenced during the moderate renal hypoperfusion caused by endotoxin.

Renal oxygenation in endotoxin shock in dogs.

Renal hemodynamics and oxygen metabolism were studied in eight adult beagle dogs during shock induced with an iv infusion of Escherichia coli endotoxin. Renal blood flow (RBF) and renal cortical PO2 decreased profoundly during the 15-min endotoxin infusion. RBF increased sharply immediately after cessation of infusion, but soon declined and remained depressed throughout the rest of the 4-h experiment. The renal cortical PO2 remained depressed for approximately 2 h and then gradually increased toward the baseline level. Endotoxin infusion was followed by an increased renal PvO2 and a decreased renal arteriovenous oxygen difference. Renal oxygen consumption declined abruptly during endotoxin infusion, but increased toward the end of the experiment. These results suggest impaired tissue oxygenation and possibly increased oxygen shunting in the kidney during endotoxin shock.

Individual relationship between heart rate and electromechanic systole in orthostatic test during autonomic blockade.

The aim of this work was to investigate the usefulness of the individual regression coefficients between the HR and the Q-A2 when studying their relationship during simultaneous changes in afterload and preload in combination with autonomic blockade. Twelve healthy male volunteers were studied in an orthostatic test done four times: without drugs (control test), after atropinization, after beta-blockade, as well as after combined beta-blockade and atropinization. The individual regression coefficients showed great inter-individual variation, and in average they were not significantly different in the four tests. However, it was observed that during the control test four, during the atropinization eight, during the beta-blockade three and during the combined beta-blockade and atropinization five individual regression coefficients were greater than -2.1, which is the regression coefficient used for the rate correction of the Q-A2 in males in the Weissler formula. It seems to use that the individual regression coefficents are useful in the evaluation of the relationship between the HR and the Q-A2 in pharmacological or physiological interventions, in which the intra-individual variation is great, and in which the number of subjects is often so small that group regressions are not very informative.

Renal lactate extraction as an indicator of tissue hypoxia in haemorrhagic hypotension.

The interrelation between the renal cortical pO2 and renal fractional extraction of arterial lactate was investigated in dogs subjected to gradual haemorrhage up to 45-50% of their blood volume. The cortical pO2, measured by means of an implanted Silastic tube, responded immediately to graded haemorrhage. The renal lactate extraction increased parallel with the arterial lactate concentration when the cortical pO2 declined from the mean initial value of 36 mmHg to 15 mmHg. A further decline of the cortical pO2 was followed by a sharp fall in the renal lactate extraction. A decrease in lactate extraction correlated closely with the cortical pO2 below 15 mmHg during severe hypoperfusion. These results suggest that the changes in the renal lactate utilization are independent of the tissue oxygen tension until the cortical pO2 decreases to the level at which the renal metabolism becomes limited by the availability of oxygen. Below this cortical pO2 the renal lactate extraction decreases in proportion to the developing tissue hypoxia.

Renal hypoxia and lactate metabolism in hemorrhagic shock in dogs.

Central and renal hemodynamics, renal cortical and medullary oxygen tension, and renal lactate metabolism were investigated in hemorrhagic shock in dogs. During graded hemorrhage, renal tissue PO2 decreased in parallel with renal blood flow, whereas renal lactate uptake remained virtually unchanged. During shock, below a mean arterial pressure (MAP) of 72 mm Hg, renal lactate utilization declined in parallel with tissue PO2. Renal lactate was produced at an MAP of 38 mm Hg. Reinfusion of shed blood increased renal tissue PO2 above its preshock value but did not restore baseline renal oxygen consumption and lactate uptake levels. These results suggest that renal lactate utilization is not limited by oxygen delivery under moderate hemorrhagic hypotension but decreases linearly with renal tissue PO2 during shock.

Heart rate variability, cardiac mechanics, and subjectively evaluated stress during simulator flight.

The effects of a simulator flight task on the heart rate variation (HRV) and hemodynamic variables were studied in nine pilots with instrument flight ratings. An electrocardiogram (ECG), phonocardiogram (PCG), and impedance cardiogram (ICG) were recorded continuously during three successive flights. Indices of HRV, power spectra, and autocorrelograms were computed from the R-R interval signal. Stroke volume (SV), cardiac output (CO), and systolic time intervals (STI) were determined by means of the ECG, PCG, and ICG. A scaling method for a subjective evaluation of tiredness, effort, and success during the flight was used. The repeats of the flight task decreased the heart rate (HR), CO, and cardiac index (CI). The different phases of the flight altered the HR (mean 97 min-1, S.E.M. 4 min-1), total HRV (RMSM) (mean 33 ms, S.E.M. 5 ms), and the periodic HRV. Subjectively, the pilots felt only moderate stress. The subjectively evaluated tiredness was significantly associated with the STI. Moderate informative stress in the flight simulator affected the chronotropic parameters of the heart. The inotropic state of the heart was not affected by the different phases of the flight but possibly by the diminishing sympathetic drive with accommodation during the repeats.

Distribution of renal cortical and Medullary tissue oxygenation in hemorrhagic shock.

Renal cortical and medullary tissue oxygen tension, systemic oxygen supply as well as central and renal hemodynamics were investigated in dogs during graded hemorrhage and subsequent reinfusion of shed blood. The measurements of tissue gas tension were carried out by means of implanted Silastic tubes. The baseline renal cortical PO2 was 35 mmHg and the corresponding medullary PO2 25 mmHg. The lowest mean cortical and medullary oxygen tensions--8 and 12 mmHg, respectively--were recorded during the severest hypotension at 40% blood loss. After reinfusions of shed blood the cortical PO2 underwent a transient increase to the original preshock level decreasing slowly thereafter. Concomitantly, the medullary PO2 reached the prehemorrhage value remaining then stationary until the end of the experiment. Arterial blood PO2 was normal throughout the study. Renal venous PO2 fell during the deepest shock but consistently exceeded the corresponding tissue PO2 levels. It is concluded that hemorrhagic hypotension impaired tissue oxygenation of both cortex and medulla, the effect being greatest in the cortex.