Circulatory recovery is as fast with air ventilation as with 100% oxygen after asphyxia-induced cardiac arrest in piglets.

We investigated return of spontaneous circulation and of cerebral oxygenation after asphyxia-induced cardiac arrest, using ventilation with air, throughout, or with 100% oxygen for a shorter or longer period. Arterial pressure, heart rate, regional cerebral oxygen saturation (CrSO2), and brain tissue oxygen tension (PbtO2) were measured in 1-d-old piglets that were hypoventilated with air and left in apnea until cardiac arrest. They were randomly assigned to be resuscitated with air (n = 13), or with oxygen for 3 (n = 12) or 30 min (n = 13) and then with air. Nine, 10, and 10 animals, respectively, needed closed chest cardiac massage. One, none, and one, respectively, died. Median (quartile range) times from start of ventilation until heart rate reached 150 bpm were 67 (60-76), 88 (76-126), and 68 (56-81) s. They were not significantly different, nor were the arterial pressure responses, times until CrSO2 reached 30%, or times until PbtO2 had increased by 0.1 kPa from its nadir. Peak PbtO2 values during resuscitation were 4.2 (3.3-5.4), 12 (6.4-15), and 25 (15-36) kPa. Thus, pure oxygen did not accelerate the recovery of circulation or of cerebral oxygenation, while even a brief exposure caused cerebral hyperoxia.

High brain tissue oxygen tension during ventilation with 100% oxygen after fetal asphyxia in newborn sheep.

The optimal inhaled oxygen fraction for newborn resuscitation is still not settled. We hypothesized that short-lasting oxygen ventilation after intrauterine asphyxia would not cause arterial or cerebral hyperoxia, and therefore be innocuous. The umbilical cord of fetal sheep was clamped and 10 min later, after delivery, ventilation with air (n = 7) or with 100% oxygen for 3 (n = 6) or 30 min (n = 5), followed by air, was started. Among the 11 lambs given 100% oxygen, oxygen tension (PO2) was 10.7 (1.8-56) kPa [median (range)] in arterial samples taken after 2.5 min of ventilation. In those ventilated with 100% oxygen for 30 min, brain tissue PO2 (PbtO2) increased from less than 0.1 kPa in each lamb to individual maxima of 56 (30-61) kPa, whereas in those given oxygen for just 3 min, PbtO2 peaked at 4.2 (2.9-46) kPa. The maximal PbtO2 in air-ventilated lambs was 2.9 (0.8-5.4) kPa. Heart rate and blood pressure increased equally fast in the three groups. Thus, prolonged ventilation with 100% oxygen caused an increase in PbtO2 of a magnitude previously only reported under hyperbaric conditions. Reducing the time of 100% oxygen ventilation to 3 min did not consistently avert systemic hyperoxia.

Inflation lung mechanics deteriorates markedly after saline instillation and open endotracheal suctioning in mechanically ventilated healthy piglets.

INTRODUCTION: Non-bronchoscopic bronchoalveolar lavage is an alternative to diagnostic bronchoscopy in pediatric patients, as fiberoptic bronchoscopes with aspiration channels are too large for small infants. There are many variations of the method in clinical practice, and saline instillation followed by open endotracheal suctioning is still commonly used. Lung function can deteriorate with these procedures, and we have investigated the effects on lung mechanics and oxygenation in healthy piglets. METHODS: The lungs of anesthetized and mechanically ventilated piglets were recruited with CPAP 35 cmH2O. Thereafter we instilled 5 ml of saline into the endotracheal tube, followed by three breaths from the ventilator. Saline was retrieved through a suction catheter wedged far distally in the airway. The procedure was followed by a new recruitment maneuver. Complete inspiratory/expiratory pressure - volume loops (PV-loops) were obtained just before and 5 min after saline instillation. Arterial blood gases were collected at equivalent times in 14 similar piglets submitted to exactly the same procedure. RESULTS: The inspiratory limb of the PV-loops changed markedly, as the lower inflection point was displaced towards higher pressures (P=0.004), and hysteresis measured at 15 and 30 cmH2O increased (P=0.004 and P=0.012, respectively). Although PaO2 decreased significantly (P=0.001), values after saline instillation/suctioning were still in the high normal range, that is, 22.2 +/- 2.6 kPa. CONCLUSIONS: Opening pressures of the lungs increase markedly after saline instillation/suctioning in healthy piglets. In this situation, adequate recruitment maneuvers and PEEP might prevent lung collapse and deteriorations in arterial oxygenation.

Perinatal adaptive response of the adrenal and carotid blood flow in sheep fetuses subjected to total cord occlusion.

OBJECTIVE: To investigate the perinatal adaptive response of the adrenal blood flow/adrenal fractional moving blood volume (AFMBV) and carotid blood flow (CBF), in sheep fetuses subjected to severe acute intrauterine hypoxia/asphyxia induced by total cord occlusion. METHODS: Adrenal blood flow velocity, AFMBV and CBF were measured in 13 exteriorized fetal sheep; eight of them underwent total umbilical cord occlusion to induce severe acute hypoxia/asphyxia. Five lambs were used as sham controls. Middle adrenal artery pulsatility index (MAAPI) and mean velocity (MAAMV) were recorded with pulsed Doppler ultrasound. AFMBV was estimated using power Doppler ultrasound. CBF was recorded with a transonic flowmeter. In the neonatal period, after resuscitation all lambs were followed for a 4-hour period and AFMBV and CBF were recorded. Mean arterial blood pressure (MABP) and fetal heart rate were recorded continuously. Arterial cortisol levels were measured at the beginning and at the end of the fetal and neonatal periods. RESULTS: Following the total cord occlusion, there was a significant reduction in the CBF, MABP, and heart rate and adrenal flow/AFMBV after 2, 4 and 5 min, respectively. Cortisol levels in the asphyctic lambs at the end of the cord occlusion were significantly lower than those in controls. After resuscitation, the asphyctic lambs showed increased AFMBV and cortisol levels, and reduced MABP as compared to control lambs. No differences were found in CBF, MAAPI and MAAMV. Thereafter, no differences were observed between the two groups in any of the studied parameters. At the end of the cord occlusion period, there was a significant correlation between AFMBV and MABP (r=0.69), between AFMBV and CBF (r =0.65) and between CBF and MABP (r=0.89). CONCLUSION: During severe acute intrauterine hypoxia, the fetal lamb is able to maintain the blood flow to the brain and the adrenal gland for 3-5 min. Changes in the AFMBV and the CBF were highly correlated to the changes in MABP. Adrenal FMBV and cortisol levels were higher in lamb neonates exposed to severe intrauterine asphyxia.

Incomplete protection by prophylactic surfactant against the adverse effects of large lung inflations at birth in immature lambs.

OBJECTIVE: To investigate whether preceding surfactant instillation prevents the harmful effect of large lung inflations at birth in immature lambs, and, if not, to find out for how long the immature lung remains sensitive to large inflations. DESIGN: In an exploratory study, 12 preterm lambs given surfactant at birth were randomized to receive five large lung inflations at four different times: at birth just before or immediately after surfactant treatment; at 10 min; or at 60 min of age. In a confirmatory study, 10 pairs of preterm lamb twins were all given surfactant before the first breath. One lamb in each pair was randomised to receive large lung inflations immediately after surfactant while the other twin underwent similar inflations at 10-15 min of age. SETTING: Animal laboratory. EXPERIMENTAL ANIMALS: Anaesthetized lambs delivered by cesarean section at a gestational age of 127 days. INTERVENTIONS: Surfactant supplementation at birth. Five sustained lung inflations of 16 ml/kg at different times in relation to surfactant instillation. Pressure-limited mechanical ventilation for 4 h. MEASUREMENTS AND RESULTS: The response to surfactant was assessed by ventilator settings, lung mechanics and lung histology. Preceding surfactant supplementation did not prevent the adverse effect of large lung inflations at birth on ventilatory efficiency and lung mechanics, but seemed to protect against severe lung injury. No adverse effect was seen from large lung inflations given at 10 min of age or later. CONCLUSION: Prophylactic surfactant supplementation does not fully protect against the harmful effect of large lung inflations during a short sensitive period immediately after birth.

Early adrenaline administration does not improve circulatory recovery during resuscitation from severe asphyxia in newborn piglets.

AIM OF THE STUDY: To investigate the effects of early intravenous adrenaline administration on circulatory recovery, cerebral reoxygenation, and plasma catecholamine concentrations, after severe asphyxia-induced bradycardia and hypotension. METHODS: One-day-old piglets were left in apnoea until heart rate and mean arterial pressure were less than 50 min(-1) and 25 mmHg, respectively. They randomly received adrenaline, 10 µgkg(-1) (n=16) or placebo (n=15) and were resuscitated with air ventilation and, when needed, closed-chest cardiac massage (CCCM). Eight not asphyxiated animals served as time controls. RESULTS: CCCM was required in 13 piglets given adrenaline and in 13 given placebo. Time to return of spontaneous circulation was: 72 (66-85)s vs. 77 (64-178)s [median (quartile range)] (p=0.35). Time until cerebral regional oxygen saturation (CrSO(2)) had increased to 30% was 86 (79-152)s vs. 126 (88-309)s (p=0.30). The two groups did not differ significantly in CrSO(2), heart rate, arterial pressure, right common carotid artery blood flow, or number of survivors: 13 vs. 11 animals. Plasma concentration of adrenaline, 2.5 min after resuming ventilation, was 498 (268-868)nmoll(-1) vs. 114 (80-306)nmoll(-1) (p=0.01). Corresponding noradrenaline concentrations were 1799 (1058-4182)nmoll(-1)vs. 1385 (696-3118)nmoll(-1) (ns). In the time controls, the concentrations were 0.4 (0.2-0.6)nmoll(-1) of adrenaline and 1.8 (1.3-2.4)nmoll(-1) of noradrenaline. CONCLUSION: The high endogenous catecholamine levels, especially those of noradrenaline, may explain why early administered adrenaline did not significantly improve resuscitation outcome.

Bradykinin preconditions postischemic arterial endothelial function in humans.

BACKGROUND: Arterial endothelial dysfunction is an important mechanism of tissue injury caused by ischemia-reperfusion (I/R). Earlier studies of I/R have shown that intracoronary preinfusion with 2.5-5 microg/mL bradykinin (BK) could alleviate the postischemic myocardial damage. Using an experimental human model of I/R, we investigated whether preceding infusion with BK could prevent the I/R-induced arterial endothelial dysfunction. METHODS: The left radial artery (LRA) from 16 healthy male adults, 18 to 30 years old, was submitted to I/R by completely occluding the left brachial artery with a pressure tourniquet for 20 minutes (ischemia), followed by its release (reperfusion). Prior to I/R, half of the subjects were randomly assigned to receive either BK (5 microg/mL) or saline, both being infused into the left brachial artery (0.5 mL/min, 10 min). The infusion was followed by a 10-minute drug-free period. The endothelial function of the LRA was studied by measuring the flow-mediated dilation (FMD) at baseline (prior to drug infusion), and at 15 minutes of reperfusion. In addition, baseline radial artery diameter, plasma nitrate, and von Willebrand factor were measured at these time points, and immediately before I/R (pre-I/R). RESULTS: BK had no effect on the pre-I/R plasma nitrate (p > 0.5 vs. saline) and diameter of LRA (p > 0.5 vs. baseline). At 15 minutes of reperfusion, FMD was significantly decreased in the saline group as compared to baseline (absolute dilation: 0.08 +/- 0.03 vs. 3.02 +/- 0.8 mm, respectively, p < 0.01; percentage dilation: 3 +/- 0.6 vs. 8 +/- 0.6%, respectively, p < 0.001), but it remained unaffected in the BK group (absolute dilation: 3.06 +/- 0.9 vs. 3.27 +/- 0.8 mm, respectively, p > 0.5; percentage dilation: 7 +/- 0.7 vs. 8 +/- 0.8%, respectively, p > 0.5). A similar trend was observed with regard to plasma nitrate, which remained unchanged in the BK group (37.01 +/- 4.14 vs. 39.14 +/- 4.49 micromol/L, p > 0.5) but decreased in the saline group (35.91 +/- 3.03 vs. 28.91 +/- 2.81 micromol/L, p < 0.1). CONCLUSION: Infusion of BK could protect the arterial endothelial function against I/R injury in humans, possibly in part by preserving the endothelial NO availability. The findings support the use of BK in the prevention of tissue injury due to I/R and might reveal an additional mechanism whereby ACE inhibitors exert their preconditioning effects on myocardium.

Mild hypothermia has minimal effects on the tolerance to severe progressive normovolemic anemia in Swine.

BACKGROUND: The benefits of hypothermia during acute severe anemia are not entirely settled. The authors hypothesized that cooling would improve tolerance to anemia. METHODS: Eight normothermic (38.0 +/- 0.5 degrees C) and eight hypothermic (32.0 +/- 0.5 degrees C) pigs anesthetized with midazolam-fentanyl-vecuronium-isoflurane (0.5% inspired concentration) were subjected to stepwise normovolemic hemodilution (hematocrit, 15%, 10%, 7%, 5%, 3%). Critical hemoglobin concentration (Hgb(CRIT)) and critical oxygen delivery (DO(2CRIT)), i.e., the hemoglobin concentration (Hgb) and oxygen delivery (DO2) at which oxygen consumption (VO2, independently measured by indirect calorimetry) was no longer sustained, and Hgb at the moment of death, defined prospectively as the point when VO2, decreased below 40 ml/min, were used to assess the tolerance of the two groups to progressive isovolemic anemia. RESULTS: At hematocrits of 15% and 10% (Hgb, 47 and 31 g/l), VO2 was maintained in both groups by an increase (P < 0.001) in cardiac output (CO) and extraction ratio (ER; P< 0.001) with unchanged mean arterial lactate concentration (L(art)). At hematocrit of 7% (Hgb, 22 g/l), all normothermic but no hypothermic animals had DO2-dependent VO2. No normothermic and three hypothermic animals survived to 5% hematocrit (Hgb, 15 g/l), and none survived to 3%. Hgb(CRIT) was 23 +/- 2 g/l and 19 +/- 6 g/l (mean +/- SD) in normothermic and hypothermic animals, respectively (P = 0.053). Hgb at death was 19 +/- 3 g/l versus 14 +/- 4 g/l (P = 0.015), and DO(2CRIT) was 8.7 +/- 1.7 versus 4.6 +/- 0.8 ml x kg(-1) x min(-1) (P < 0.001). CONCLUSION: During progressive normovolemic hemodilution in pigs, hypothermia did not significantly change Hgb(CRIT), but it decreased the Hgb at death, i.e., short-term survival was prolonged.

Coronary flow reserve in the newborn lamb: an intracoronary Doppler guide wire study.

Recent studies indicate a severely reduced coronary flow reserve (CFR) in neonates with congenital heart disease. The significance of these studies remains debatable, as the ability of the anatomically normal neonatal heart to increase coronary flow is currently unknown. This study was designed to establish normal values for CFR in newborns after administration of adenosine [pharmacologic CFR (pCFR)] and as induced by acute hypoxemia (reactive CFR). Thirteen mechanically ventilated newborn lambs were studied. Coronary flow velocities were measured in the proximal left anterior descending coronary artery before and after adenosine injection (140 and 280 microg/kg i.v.) using an intracoronary 0.014-in Doppler flow-wire. Measurements were made at normal oxygen saturation (SaO(2)) and during progressive hypoxemia induced by lowering the fraction of inspired oxygen. CFR was defined as the ratio of hyperemic to basal average peak flow velocity. In a hemodynamically stable situation with normal SaO(2), pCFR was 3.0 +/- 0.5. pCFR decreased with increasing hypoxemia. Regression analysis showed a linear relation between SaO(2) and pCFR (R = 0.86, p < 0.0001). Reactive CFR obtained at severe hypoxemia (Sao(2) <30%) was 4.2 +/- 0.8, and no significant further increase in coronary flow velocity occurred by administration of adenosine. Newborn lambs have a similar capacity to increase coronary flow in response to both pharmacologic and reactive stimuli as older subjects. Administration of adenosine does not reveal the full capacity of the newborn coronary circulation to increase flow, however, as the flow increase caused by severe hypoxemia is significantly more pronounced.

The hemodynamic and metabolic effects of shivering during acute normovolemic hemodilution.

UNLABELLED: To assess the hemodynamic and metabolic effects of shivering during extreme normovolemic hemodilution, we anesthetized 16 pigs with fentanyl-midazolam-pancuronium. Mild hypothermia (36.5 degrees +/- 0.1 degrees C) was induced by surface cooling, and the animals were randomized to either a control group (hemoglobin 118 +/- 3 g/L) or a hemodilution group (hemoglobin 52 +/- 2 g/L). In the latter group, blood was replaced with an isotonic Ringer's acetate/dextran 70 solution. Shivering was allowed to occur by a controlled decrease in the infusion rate of pancuronium. Shivering increased oxygen consumption (VO(2)) in both groups (P < 0.001). Initially, this was predominantly compensated for by an increased oxygen extraction ratio (ER), but when VO(2) was 2.3 +/- 0.2 times baseline, critical levels of mixed venous oxygenation (SVO(2) = 18% +/- 2%; PVO(2) = 22.5 +/- 1.5 mm Hg) and ER (82% +/- 3%) were recorded in anemic animals. Control animals did not reach critical levels until VO(2) was maximal (3.7 +/- 0.3 times baseline). Maximal attained VO(2) was less (2.9 +/- 0.1 times baseline) in the anemic animals (P = 0.01), and at this stage two of these pigs had myocardial lactate production, one of which died in ventricular fibrillation. Coronary perfusion pressure was significantly less (P < 0.001) in the anemic animals. We conclude that in this experimental model, maximal shivering as measured by VO(2) was limited in hemodiluted animals, and left ventricular oxygen balance was marginal, as evidenced by a decreased lactate uptake and extraction. IMPLICATIONS: The effect of acute increases in oxygen consumption (shivering) on severely anemic individuals has not been evaluated. In this experimental model, left ventricular oxygen balance was marginal, as evidenced by decreased lactate extraction.

Different responses of myocardial and cerebral blood flow to cord occlusion in exteriorized fetal sheep.

Type and duration of fetal asphyxial insult affect the distribution of blood flow to the heart and brain. The purpose of this study was to describe dynamic and quantitative changes in regional myocardial and cerebral blood flow (CBF) during fetal asphyxia induced by total occlusion of the umbilical cord. Eleven exteriorized fetal sheep were subjected to total umbilical cord occlusion and five fetal sheep served as sham controls. Regional blood flow (BF) to the brain and heart was quantified using radioactive microspheres before and after 5 min of occlusion and finally when fetal mean arterial blood pressure had decreased below 25 mm Hg, 9.8 (0.8) [mean (SD)] min after occlusion. Right coronary arterial (RCA) blood flow velocity and carotid BF were registered continuously. Mean values of arterial pH and oxygen content (mL O(2)/100 mL) were 7.08 (0.11) and 4.4 (2.9) before cord occlusion and decreased to 6.83 (0.05) and 1.4 (0.9) at 5 min after occlusion (p < 0.01, respectively). Carotid BF was significantly below preocclusion values by 2.5 min (p < 0.05), whereas RCA velocity time integral per minute remained above preocclusion values for 9 min. CBF decreased from 316 (24) before cord occlusion to 156 (30) mL/min/100 g at 5 min (p < 0.01), whereas right myocardial BF was maintained at 792 (125) and 751 (183) mL/min/100 g, respectively. CBF decreased rapidly after total cord occlusion whereas myocardial BF increased and was maintained until shortly before cardiac arrest, suggesting the myocardium to be better preserved during this type of insult in already partially asphyxiated fetuses.