Myocardial calcium overload during graded hypothermia and after rewarming in an in vivo rat model.

AIM: Mechanisms underlying cardiac contractile dysfunction during and after rewarming from hypothermia remain largely unknown. We have previously reported myocardial post-hypothermic calcium overload to be the culprit. The aim of the present study was to measure changes in myocardial [Ca(2+) ](i) during graded hypothermia and after rewarming in an anesthetized, intact rat model, using the (45) Ca(2+) technique. METHODS: Rats were randomized and cooled to 15 °C. Hearts were excised and perfusion-washed to remove extracellular calcium after 0.5 h of hypothermia (n = 9), 4 h of hypothermia (n = 8), and after 4 h of hypothermia and 2 h rewarming (n = 9). A normothermic group, kept at 37 °C for 5 h, served as control (n = 6). [Ca(2+) ](i) was determined in perchloric acid extracts of heart tissue. Spontaneous cardiac electromechanic work was maintained during hypothermia without cardiac arrest or ischaemia. RESULTS: Between 0.5 and 4 h at 15 °C, a six-fold increase in cardiac [Ca(2+) ](i) was observed (0.55 ± 0.10 vs. 2.93 ± 0.76 µmol (g dry wt)(-1) ). Rewarming resulted in a 33% decline in [Ca(2+) ](i) , but the actual value was significantly above the value measured in control hearts. CONCLUSION: We show that calcium overload is a characteristic feature of the beating heart during deep hypothermia, which aggravates by increasing duration of exposure. The relatively low decline in [Ca(2+) ](i) during the rewarming period indicates difficulties in recovering calcium homoeostasis, which in turn may explain cardiac contractile dysfunction observed after rewarming.

Altered brain myelin sheath morphology after rewarming in situ.

In this study cerebral ultrastructure was examined in an in vivo rat model, after rewarming from profound hypothermia (15-13 degrees C). Animals held at 37 degrees C served as controls. After rewarming, brains were examined by electron microscope. Micrographs were taken randomly, analyzed anonymously, and quantified by morphometry. Serum analysis of the stress marker S-100beta was carried out in identical groups. The most striking findings in rewarmed animals, when compared to controls, were alterations of myelin sheaths (p<.008) and elevated S-100beta (p<.0001). This indicates that cells in the central nervous system are susceptible to injury in an experimental model of accidental hypothermia and rewarming.

A controlled comparison between single doses of intravenous and intramuscular morphine with respect to analgesic effects and patient safety.

UNLABELLED: BACKGROUND AND AIM OF INVESTIGATION: Intramuscular (IM) administration has been considered to be safer than intravenous (IV) for opioids on wards, but a comparative knowledge of patient safety and analgesic potency following a single dose of IV and IM administration is lacking. This study was carried out to compare patient safety and analgesic efficacy of a single and high dose of morphine given IM or IV for post-operative pain management. MATERIALS AND METHODS: Thirty-eight patients with post-operative pain following hip replacement surgery were given IM or IV morphine 10 mg at a specified pain level. The study was randomized and double blinded. Time to onset of analgesic effect (11-point numeric rating scale), respiratory function (p(a)CO2, p(a)O2, and respiratory rate), level of sedation (5-point verbal rating scale), and hemodynamic function were recorded. RESULTS: In the IV group there was a slight but significant increase in p(a)CO2 after 5, 10, and 15 min compared with the IM group (5.2 vs. 4.8, 5.4, vs. 5.0 and 5.5 vs. 5.1 kPa, respectively). The IV group had a significantly faster onset of analgesic effect than the IM group (5 vs. 20 min). Between 5 and 25 min after morphine administration, pain status in the IV group was significantly improved compared with the IM group. Patients in the IV group were slightly more sedated than the IM group 5 and 10 min after morphine. CONCLUSION: A 10 mg bolus dose of IV morphine given to patients with moderate pain after surgery does not cause severe respiratory depression, but provides more rapid and better initial analgesia than 10 mg given IM. IV morphine even at a dose as high as 10 mg IV is well tolerated if there is a certain level of pain at its administration. The safety of IV morphine on the general ward needs to be further explored in adequately controlled studies.

Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery.

AIM: To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery. METHODS: This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramuscularly (IM). Arterial blood and CSF samples (from a spinal catheter) were drawn simultaneously at 10, 30, 60, and 120 min after administration. Morphine and metabolites [morphine-3-glucuronide (M-3-G), morphine-6-glucuronide (M-6-G), and normorphine (NM)] were determined by a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Thirty-eight patients were included: 13 men and 25 women, 20 in the IV, 18 in the IM group. Serum concentrations of M after 10 min were consistently higher after IM than IV, concentrations of M-3-G and M-6-G after IM surpassed those of IV after 45 min. NM was not found. None of the metabolites was found in CSF. CSF morphine concentrations and CSF/serum concentration ratios were consistently higher after IV compared to IM. The mean AUC(CSF)/AUC(serum) (0-120 min) concentration ratios were 0.18 and 0.09 after IV and IM, respectively. CONCLUSIONS: The uptake of morphine to the CSF was consistently higher after IV administration than after IM already after 10 min. The higher CSF concentration may be caused by an initially higher morphine blood/CSF gradient following IV morphine injection. The pharmacokinetic findings are compatible with a more rapid and extensive initial effect of IV morphine compared with IM.

Cardiovascular effects of epinephrine during rewarming from hypothermia in an intact animal model.

Rewarming from accidental hypothermia is often complicated by "rewarming shock," characterized by low cardiac output (CO) and a sudden fall in peripheral arterial pressure. In this study, we tested whether epinephrine (Epi) is able to prevent rewarming shock when given intravenously during rewarming from experimental hypothermia in doses tested to elevate CO and induce vasodilation, or lack of vasodilation, during normothermia. A rat model designed for circulatory studies during experimental hypothermia and rewarming was used. A total of six groups of animals were used: normothermic groups 1, 2, and 3 for dose-finding studies, and hypothermic groups 4, 5, and 6. At 20 and 24 degrees C during rewarming, group 4 (low-dose Epi) and group 5 (high-dose Epi) received bolus injections of 0.1 and 1.0 microg Epi, respectively. At 28 degrees C, Epi infusion was started in groups 4 and 5 with 0.125 and 1.25 microg/min, respectively. Group 6 served as saline control. After rewarming, both CO and stroke volume were restored in group 4, in contrast to groups 5 and 6, in which both CO and stroke volume remained significantly reduced (30%). Total peripheral resistance was significantly higher in group 5 during rewarming from 24 to 34 degrees C, compared with groups 4 and 6. This study shows that, in contrast to normothermic conditions, Epi infused during hypothermia induces vasoconstriction rather than vasodilation combined with lack of CO elevation. The apparent dissociation between myocardial and vascular responses to Epi at low temperatures may be related to hypothermia-induced myocardial failure and changes in temperature-dependent adrenoreceptor affinity.

Effects of sympathetic stimulation during cooling on hypothermic as well as posthypothermic hemodynamic function.

This experimental study was performed to explore hemodynamic effects of a moderate dose epinephrine (Epi) during hypothermia and to test the hypothesis whether sympathetic stimulation during cooling affects myocardial function following rewarming. Two groups of male Wistar rats (each, n=7) were cooled to 15 degrees C, maintained at this temperature for 1 h, and then rewarmed. Group 1 received 1 microg/min Epi, i.v., for 1 h during cooling to 28 degrees C, a dose known to elevate cardiac output (CO) by approximately 25% at 37 degrees C. Group 2 served a saline solution control. At 37 degrees C, Epi infusion elevated CO, left ventricular systolic pressure, maximum rate of left ventricle pressure rise, and mean arterial pressure. During cooling to 28 degrees C, these variables, with the exception of mean arterial pressure, decreased in parallel to those in the saline solution group. In contrast, in the Epi group, mean arterial pressure remained increased and total peripheral resistance was significantly elevated at 28 degrees C. Compared with corresponding prehypothermic values, most hemodynamic variables were lowered after 1 h at 15 degrees C in both groups (except for stroke volume). After rewarming, alterations in hemodynamic variables in the Epi-treated group were more prominent than in saline solution controls. Thus, before cooling, continuous Epi infusion predominantly stimulates myocardial mechanical function, materialized as elevation of CO, left ventricular systolic pressure, and maximum rate of left ventricle pressure rise. Cooling, on the other hand, apparently eradicates central hemodynamic effects of Epi and during stable hypothermia, elevation of peripheral vascular vasopressor effects seem to take over. In contrast to temperature-matched, non-Epi stimulated control rats, a significant depression of myocardial mechanical function occurs during rewarming following a moderate sympathetic stimulus during initial cooling.

Morphologic changes in tubular cells from in situ kidneys following experimental hypothermia and rewarming.

Although renal failure may occur following rewarming from deep accidental hypothermia, this subject has received little attention in experimental hypothermia and clinical case reports. In order to explore the integrity of hypothermic and posthypothermic renal morphology we used an experimental animal model of accidental hypothermia where the heart supports the circulation throughout cooling and rewarming without accompanying cardioplegia or ischemia. Ultrastructural changes in renal tubular cells from three groups of pentobarbital anesthetized Wistar rats: 1) controls (n=6) maintained at 37 degrees C for 4 h, 2) hypothermic rats (n=6) core-cooled and maintained at 15-13 degrees C for 4 h, and 3) rewarmed rats (n=10), were studied as a sensitive indicator of renal damage. Electron micrographs (EM) from hypothermic kidneys showed rounded up mitochondria with loss of contrast. These changes were observed in several though not all of the biopsies, but they were found in all kidneys. Areas exhibiting focal tubular necrosis were seen on most EM from three of these kidneys. EM from rewarmed kidneys showed alterations of mitochondrial ultrastructure with similarities to those observed after hypothermia, but in general the changes were more prominent. Extracellular edema, intracellular edema, swelling of mitochondria, margination of chromatin, necrosis of single tubular cells, and disrupting necrotic debris into tubular lumen could be found in micrographs from 7 of the 10 kidneys examined. Rewarming from experimental hypothermia, without episodes of ischemia or hypoxia, thus induces ultrastructural changes in renal tubular cells similar to changes observed in acute tubular necrosis, associated with renal failure.

Physiological and haematological responses to cold exposure in the elderly.

Throughout Europe, including Norway, increased winter mortality from cardiovascular diseases (CVD) is well described. However, while there are associations between high CVD mortality and cold climate, the reason for the excess deaths is not entirely known. Recent epidemiological evidence suggests that brief outdoor exposure to cold conditions may be linked to increased winter mortality in the elderly. However, the question as to whether alterations in the haemostatic system following exposure to cold could be responsible for the increased winter risk has been little investigated in elderly subjects. In this study, we have compared the effect of exposing lightly clothed healthy elderly men and women (60-70 years) for 90 minutes to either a mild cold stress (16 degrees C) or thermoneutral conditions (28 degrees C). Measurements of a variety of autonomic and haematological parameters were made in order to compare to what extent exposure to cold stress affects production of thrombogenic risk factors. The overall autonomic responses clearly showed that the subjects were mildly cold exposed. The main changes in the blood system were a cold exposure increase in hemoconcentration and an increase in the fibrinolytic parameter, t-PA. This coupled with other changes support previous findings and it is concluded that short term mild cold exposure in the elderly initiates a mild inflammatory reaction and a tendency for an increased state of hypercoagulability.

Rewarming from hypothermia. Newer aspects on the pathophysiology of rewarming shock.

The fatal circulatory derangements often observed when resuscitating victims of accidental hypothermia by rewarming are recognized as a falling cardiac output and a sudden drop in blood pressure, termed "rewarming shock". The real cause of this rewarming shock, or rewarming collapse, is, so far, unknown. This review presents current information exploring different aspects of the compromised circulatory function during hypothermia and especially after rewarming and supports the hypothesis that posthypothermic circulatory instability may be caused by cardiac insufficiency and alteration of the peripheral vascular bed. Cellular calcium overload, disturbed calcium homeostasis, changes in myocardial myofilament responsiveness to intracellular calcium as well as impaired high energy phosphate homeostasis could all be proposed as important factors leading to the changes observed in the hypothermic heart. Together with alteration of capillary function, increased capillary leakage of plasma protein, changes in intra- and extravascular volume-homeostasis and alteration of autonomous vascular control they all contribute to a maintained low cardiac output during and after rewarming which is associated with a fatal outcome.

Coronary endothelium-derived vasodilation during cooling and rewarming of the in situ heart.

The integrity of coronary vascular endothelial vasodilator function during core cooling and rewarming was investigated in a pentobarbital-anesthetized open-chest dog model. Vasodilator response was assessed as the change from baseline blood flow by injecting the endothelial-dependent vasodilator acetylcholine (ACh) (1.0 microg) or the endothelial-independent vasodilator nitroglycerin (NTG) (50 microg) into the left anterior descending (LAD) coronary artery. Change in blood flow was measured using a transit time ultrasonic volume flowmeter technique. During cooling and rewarming LAD blood flow was significantly decreased. After rewarming, aortic pressure was artificially elevated to reach control. This procedure restored heart work (LV-RPP, left ventricular rate pressure product) and coronary perfusion pressure, but LAD blood flow remained lowered. Ability to dilate the vascular bed supplied by LAD, after injections of ACh or NTG, was present both during cooling and rewarming. At 25 degrees C coronary blood flow (LAD) increased from 3 +/- 1 to 9 +/- 1 mL x min(-1) in response to both ACh and NTG. Posthypothermic blood flow increased from 7 +/- 1 to 19 +/- 2 and 20 +/- 3 mL x min(-1) in response to ACh and NTG, respectively. Measured as the percent change from baseline LAD blood flow, the response was not significantly different from the one obtained in prehypothermic hearts. In conclusion, coronary vasodilator function, both endothelium dependent and endothelium independent, is present but not maintained at the same level during cooling to 25 degrees C and rewarming. In spite of the deterioration of cardiac function, no selective defect in the endothelium-dependent response was detected, either during hypothermia or after rewarming.

The effect of short-term cold exposure on risk factors for cardiovascular disease.

The aim of this study was to see if a short-term period of exposure to cold in young healthy subjects causes changes in hematological factors known to be associated with the promotion of thrombogenesis. Over a period of 48 hours, changes in the distribution of erythrocytes, granulocytes, and blood platelets, as well as several coagulation, inflammatory, and fibrinolytic parameters, were monitored in 11 young healthy male subjects following a short period (1 hour) of cold exposure (CE) (ambient temperature, 11 degrees C) or exposure to thermoneutral conditions (ambient temperature, 26 degrees C) in winter (November). The major findings were: (1) a CE-induced hemoconcentration as indicated by an increase in erythrocyte count (3.2% increase); (2) after appropriate adjustments for changes in hemoconcentration, a cold-induced mobilization of granulocytes (14.5% increase) and a cold-induced decrease in lymphocytes (7% decrease); (3) thromboxane B2 release following endotoxin stimulation of whole blood was increased by 27.4% in the CE experiments; (4) diurnal rhythms were observed in granulocytes, blood platelets, middle plate volume, tissue plasminogen activator, and plasma activator inhibitor; and (5) CE caused no significant changes in lipopolysaccharide-induced tissue factor, nor in the blood coagulation factor VII or cytokines, interleukin-6, and tumor necrosis factor. It is concluded that short-term cold exposure in young healthy subjects initiates a mild inflammatory reaction and a tendency for an increased state of hypercoagulability.

Left ventricular dysfunction following rewarming from experimental hypothermia.

This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction persisting after rewarming the unsupported in situ dog heart could be characterized as a systolic, diastolic, or combined disturbance. Core temperature of 8 mongrel dogs was gradually lowered to 25 degreesC and returned to 37 degreesC over a period of 328 min. Systolic function was described by maximum rate of increase in left ventricular (LV) pressure (dP/dtmax), relative segment shortening (SS%), stroke volume (SV), and the load-independent contractility index, preload recruitable stroke work (PRSW). Diastolic function was described by the isovolumic relaxation constant (tau) and the LV wall stiffness constant (Kp). Compared with prehypothermic control, a significant decrease in LV functional variables was measured at 25 degreesC: dP/dtmax 2,180 +/- 158 vs. 760 +/- 78 mmHg/s, SS% 20.1 +/- 1.2 vs. 13.3 +/- 1.0%, SV 11.7 +/- 0.7 vs. 8.5 +/- 0.7 ml, PRSW 90.5 +/- 7.7 vs. 29.1 +/- 5.9 J/m. 10(-2), Kp 0.78 +/- 0.10 vs. 0.28 +/- 0.03 mm-1, and tau 78.5 +/- 3.7 vs. 25.8 +/- 1.6 ms. After rewarming, the significant depression of LV systolic variables observed at 25 degreesC persisted: dP/dtmax 1,241 +/- 108 mmHg/s, SS% 10.2 +/- 0.8 J, SV 7.3 +/- 0.4 ml, and PRSW 52.1 +/- 3.6 m. 10(-2), whereas the diastolic values of Kp and tau returned to control. Thus hypothermia induced a significant depression of both systolic and diastolic LV variables. After rewarming, diastolic LV function was restored, in contrast to the persistently depressed LV systolic function. These observations indicate that cooling induces more long-lasting effects on the excitation-contraction coupling and the actin-myosin interaction than on sarcoplasmic reticulum Ca2+ trapping dysfunction or interstitial fluid content, making posthypothermic LV dysfunction a systolic perturbation.

Glucose and fatty acid oxidation by the in situ dog heart during experimental cooling and rewarming.

BACKGROUND: Reduced myocardial function after hypothermia may be metabolic in origin, but the relationship between myocardial metabolism and the various components of hypothermia-mediated dysfunction has not been thoroughly investigated. METHODS: In the present study we measured myocardial uptake and oxidation of glucose and oleate in mongrel dogs undergoing cooling to 25 degrees C followed by rewarming to 37 degrees C, using radiolabeled substrates. RESULTS: Segment work index declined from 39.3 +/- 5.1 to 15.1 +/- 2.4 mm Hg in response to cooling from 37 degrees to 25 degrees C and did not recover completely on rewarming (27.2 +/- 4.2 mm Hg, p < 0.05). Oleate uptake declined from 3,251 +/- 619 to 1,043 +/- 356 nmol.min-1.100 g-1 (p < 0.05) when the dogs were cooled from 37 degrees to 25 degrees C. Simultaneously, oxidation rate fell from 1,089 +/- 158 to 354 +/- 83 nmol.min-1.100 g-1 (p < 0.05). On rewarming, oleate uptake was restored to prehypothermic values, whereas its rate of oxidation remained depressed (480 +/- 129 nmol.min-1.100 g-1; p < 0.05). Uptake and oxidation of glucose also declined significantly during cooling. However, both uptake and oxidation of glucose recovered fully on rewarming. CONCLUSIONS: The results of the present study demonstrate a reduced capacity to oxidize fatty acids by the myocardium during rewarming after hypothermia.

Changes in myocardial ultrastructure induced by cooling as well as rewarming.

The aim of the present study was to investigate if hypothermia and rewarming, without accompanying cardiac ischaemia or cardioplegia, causes myocardial damage. Anaesthetized rats were subjected to a cooling procedure (4 h at 15-13 degrees C) where spontaneous cardiac electromechanical activity was maintained, followed by rewarming. Control rats, hypothermic rats and posthypothermic rats were perfusion-fixed, the hearts removed and the ventricles examined using an electron microscope. Based on morphometric methodology volume fractions as well as absolute volumes of cellular and subcellular components of the ventricles were assessed. In hypothermic hearts capillary volume fraction was significantly decreased, which was probably due to a decrease in perfusion pressure. The cytosolic volume increased in both absolute values and as a fraction of the myocyte: from 25 +/- 11 in controls to 43 +/- 8 microliters and from 0.067 +/- 0.023 to 0.102 +/- 0.013, respectively. There was a corresponding relative decrease in the volume fraction of myofilaments from 0.598 +/- 0.030 to 0.548 +/- 0.024. In posthypothermic hearts significant tissue swelling was apparent, dominated by a significant increase in myocyte volume from 372 +/- 66 in controls to 522 +/- 166 microliters. Similar changes were measured in mitochondrial and cytosolic volumes. In conclusion, the myocardial ultrastructure was altered during hypothermia as well as after rewarming. Posthypothermic myocardium showed generalized cellular swelling and areas of cellular necrosis.

Increase in leukotrienes in the coronary circulation by cooling: a study in the anesthetized dog.

Pentobarbital-anesthetized dogs were instrumented for hemodynamic measurements and cooled by heat exchange tubes. Through a catheter in the coronary sinus, blood samples were obtained and plasma leukotrienes measured using a high-pressure liquid chromatography technique. Hemodynamic function was significantly reduced during cooling, and during subsequent rewarming hemodynamic function was only partly restored. Leukotriene C4 and B4 were significantly increased at a body core temperature of 31 degrees C and 25 degrees C during cooling but not during rewarming (28 degrees C) and after rewarming (37 degrees C). This indicates that during decreasing body temperature elevated leukotriene levels may increase vascular permeability, inflammation, and vasoactivity and counteract temperature-dependent decrease in these functions. Disturbed microcirculation may thus diminish cardiac recovery during rewarming.

Changes in blood flow distribution and capillary function after deep hypothermia in rat.

The present experiments were carried out in the rat to investigate the peripheral vascular function prior to the development of posthypothermic circulatory collapse. In the first study, mean arterial blood pressure, heart rate, cardiac output, regional blood flow, and plasma volume of hypothermic (4 h, 15-13 degrees C) and rewarmed rats were compared with normothermic controls. In response to hypothermia, arterial blood pressure, heart rate, and cardiac output declined markedly. After rewarming, arterial blood pressure and heart rate recovered fully, whereas cardiac output was only 33 +/- 7% of the control value (p < 0.025). Tissue blood flow was markedly depressed during hypothermia (p < 0.025), except for the abdominal skin. After rewarming, blood flow in skeletal muscle returned to within control levels, whereas blood flow in internal organs remained low (p < 0.025 vs. control). Posthypothermic plasma volume was 77 +/- 3% of control (p < 0.05). In the second study, the transcapillary colloid osmotic pressure gradient (COPp-COPi) was calculated following measurement of colloid osmotic pressure in plasma (COPp) and interstitium (COPi) in prehypothermic, hypothermic, and posthypothermic rats. The posthypothermic value of COPp-COPi was 76 +/- 4% of the prehypothermic value (p < 0.05). In conclusion this study demonstrates that the reduced cardiac output in rewarmed rats is associated with an altered regional blood flow distribution compared with that of normal rats. Capillary integrity also seemed perturbed. Thus, changes in both control and function of the peripheral vasculature are important mechanisms in the development of a posthypothermic circulatory collapse.

Experimental hypothermia and rewarming: changes in mechanical function and metabolism of rat hearts.

Rewarming from accidental hypothermia is associated with fatal circulatory derangements. To investigate potential pathophysiological mechanisms involved, we examined heart function and metabolism in a rat model rewarmed after 4 h at 15-13 degrees C. Hypothermia resulted in a significant reduction of left ventricular (LV) systolic pressure, cardiac output, and heart rate, whereas stroke volume increased. The maximum rate of LV pressure rise decreased to 191 +/- 28 mmHg/s from a control value of 9,060 +/- 500 mmHg/s. Myocardial tissue content of ATP, ADP, and glycogen was significantly reduced, whereas lactate content remained unchanged. After rewarming, heart rate returned to control value, whereas LV systolic pressure, cardiac output, and stroke volume all remained significantly depressed. The posthypothermic maximum rate of LV pressure rise was 5,966 +/- 1.643 mmHg/s. The posthypothermic myocardial lactate content was significantly increased (to 13.3 +/- 3.2 nmol/mg from control value of 5.7 +/- 1.9 nmol/mg), and ATP and glycogen remained significantly lowered. Creatine phosphate or energy charge did not change significantly during the experiment. The finding of deteriorated myocardial mechanical function and a shift in energy metabolism shows that the heart could be an important target during hypothermia and rewarming in vivo, thus contributing to the development of a posthypothermic circulatory collapse.

Endothelin-1 causes accumulation of leukocytes in the pulmonary circulation.

We previously reported that the endothelin-1 (ET-1)-induced increase in microvascular permeability in isolated rat lungs required leukocytes in the perfusate. The present study examines whether intravenous administration of ET-1 in rats causes an inflammatory reaction in the lungs. Histological examination of the lung specimens 2 hr following ET-1 infusion showed adhesion of leukocytes to the vascular endothelium in pulmonary vessels and sequestration of leukocytes in the pulmonary capillaries. Microscopic examination of the bronchoalveolar lavage fluid revealed that leukocytes had migrated into the alveoli. Simultaneously a depletion of peripheral blood leukocytes was observed. These effects were reversible by 24 hr. Monitoring of systemic hemodynamic effects showed a continued reduced cardiac stroke volume and increasing heart rate after 2 hr. In isolated rat lungs, ET-1 caused a rapid increase in pulmonary artery pressure, pulmonary microvascular pressure, and edema formation. Compared with Krebs-albumin-perfused lungs, blood-perfusion accelerated the edemagenic effect of ET-1. ET-1 plays a role in the regulation of leukocyte-endothelial cell interactions in the pulmonary circulation. This has potential importance for the edemagenic effect of ET-1.

Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow, and myocardial metabolism in dogs.

Conflicting results have been reported as to the extent that cardiovascular function can be reestablished after rewarming from hypothermia. We measured hemodynamic function, myocardial metabolism and tissue water content in dogs core-cooled to 25 degrees C and later rewarmed. At 25 degrees C left ventricular (LV) systolic pressure (LVSP) was 54% +/- 4%, maximum rate of LV pressure rise (LV dP/dtmax) 44% +/- 5%, aortic pressure (AOP) 50% +/- 6%, heart rate (HR) 40% +/- 0%, cardiac output (CO) 37% +/- 5%, myocardial blood flow (MBF) 34% +/- 5%, and myocardial oxygen consumption (MVO2) 8% +/- 1%, compared to precooling. Stroke volume (SV) and LV end-diastolic pressure (LVEDP) were unchanged. As normothermia (37 degrees C) was reestablished, the depression of cardiac function and myocardial metabolism remained the same as that at 25 degrees C: LVSP 71% +/- 6%, LV dP/dtmax 73% +/- 7%, SV 60% +/- 9%, AOP 70% +/- 6%, CO 57% +/- 9%, MBF 53% +/- 8%, and MVO2 44% +/- 8% HR, in contrast, recovered to precooling values. The arterial concentrations of glucose and free fatty acids (FFA) did not change significantly during the experimental period, whereas an increase in lactate of nonmyocardial origin appeared after rewarming. Increased myocardial contents of creatine phosphate and water were found during both hypothermia and rewarming. The present study demonstrates a persistent depression of cardiac function after hypothermia and rewarming in spite of adequate energy stores. Thus, a direct influence on myocardial contractile function by the cooling and rewarming process is suggested.

Changes in ventricular fibrillation threshold during acute hypothermia. A model for future studies.

Hypothermia and rewarming are associated with an increased incidence of lethal arrhythmias in man. The relationship between reduction in body temperature and ventricular fibrillation threshold was studied in 7 pentobarbital anaesthetized dogs using programmable electrical stimulation while cooling and rewarming between 37 degrees C and 25 degrees C in steps of 3 degrees C. Fibrillation threshold was defined as the number of extrastimuli required to evoke ventricular fibrillation. QRS-durations and corrected QT-intervals (QTc) were measured from surface electrocardiograms. Monophasic action potential durations were recorded from the base and apex of the heart. Fibrillation threshold decreased with decreasing temperatures; e.g., at 37 degrees C ventricular fibrillation was not inducible after 5 extrastimuli, while at 25 degrees C only 2 extrastimuli were required. From 37 degrees C to 25 degrees C QRS-width, monophasic action potential durations and QTc increased while conduction velocity decreased. The differential effects on conduction and monophasic action potential duration provide a basis for induction of ventricular fibrillation during acute hypothermia. This model of hypothermia-induced ventricular fibrillation should prove useful for future studies aimed at understanding the mechanisms responsible for hypothermia-related deaths.