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A patient with severe hypothermia was in ventricular fibrillation for more than 1 hour. Conservative core rewarming methods were used with complete success. In dealing with severely hypothermic patients, it is important to continue treatment despite prolonged cardiopulmonary arrest. If conservative core rewarming methods are not successful, then aggressive invasive techniques might be effective.
Thirty patients with post-operative hypothermia following major surgery (thoracic, abdominal, orthopaedic) were allocated randomly to either active warming with a radiant heater (500 W) or passive rewarming with a reflective blanket. Rectal temperature, mean skin temperature (at four measuring sites), continuous haemoglobin saturation and shivering were measured for 2 h post-operatively. Although post-operative heat supply with a radiant heater resulted in faster rewarming, there were no differences between the two groups with respect to haemoglobin saturation and shivering.
BACKGROUND: Impairment of microcirculation due to endothelial cell damage must be considered a limiting factor in organ preservation. The present study aims at a quantitative assessment of preservation-induced injury in cultured human endothelial cells. METHODS: Monolayer cultures of human umbilical vein endothelial cells were exposed to cold (40 degrees C) hypoxic storage in University of Wisconsin solution, histidine-tryptophane-ketoglutarate solution, Euro-Collins solution, and saline solution. Cellular integrity was evaluated by viable cell count, ultrastructural analysis, and prostacyclin release after 24, 48, and 72 hours of storage and subsequent 6 hours of reincubation in culture medium at 37 degrees C. Expression of intercellular adhesion molecule-1 was investigated after 6, 12, and 24 hours of cold preservation and after 6 hours of rewarming. RESULTS: Cellular viability was best maintained with University of Wisconsin and histidine-tryptophane-ketoglutarate solutions with no significant reduction of cell count up to 72 hours; Euro-Collins solution and saline solution caused a significant decline in cell numbers after 24 hours (p < 0.05). Morphology was best preserved by University of Wisconsin solution. Prostacyclin values were elevated after 24 hours in Euro-Collins solution and saline solution, after 48 hours in histidine-tryptophane-ketoglutarate, Euro-Collins, and saline solutions, and after 72 hours in Euro-Collins solution (p < 0.05, compared with University of Wisconsin solution). ICAM expression was weak after cold storage (24 hours) in University of Wisconsin solution, moderate after incubation in histidine-tryptophane-ketoglutarate and Euro-Collins solutions and intensive after storage in saline solution. In contrast, rewarming caused intensive expression of intercellular adhesion molecule-1 in all experimental groups as compared with controls, which showed baseline expression at any time. CONCLUSIONS: From our results we conclude that in this model cellular integrity is best protected by University of Wisconsin solution, increased prostacyclin release is consistent with morphologic alterations and intercellular adhesion molecule-1 expression is clearly up-regulated in endothelial cells under reperfusion conditions after cold hypoxic storage.
A case of cardiopulmonary arrest due to accidental hypothermia and its successful therapy is described. A 46-year-old man with deep accidental hypothermia (25.3 degrees C esophageal) was found outside showing respiratory and cardiac arrest. Resuscitation was immediately started and continuously performed during the transport to the University Hospital of Rostock, where a treatment with extracorporeal circulation was possible. After cardiopulmonary resuscitation for 120 minutes, the patient could finally be connected to the extracorporeal circulation. Over a period of 130 minutes the patient could be rewarmed up to a body temperature of 36.0 degrees C. The following therapy was complicated by the development of an alcoholic delirium, which was treated by clomethiazol, droperidol and clonidin infusion. After seven days of intensive therapy, he recovered completely and could be transferred from the intensive care unit to the department of psychiatry without neurological deficits showing only healing of frostbite of the feet. Based on this case report, the use of extracorporeal circulation for adequate rewarming in combination with cardiopulmonary resuscitation is described. Compared to other therapeutic measures such as peritoneal dialysis or veno-venous haemofiltration treatment with extracorporeal circulation is the method of choice.
Thirty-one anesthetized dogs were surface cooled at 5 C and rewarmed after a variable period. Respiration was controlled with a volume respirator. When cardiac arrest occurred, circulation was provided with the mechanical ventricular assistance (MVA) device in 23 dogs. Of the animals maintained for four hours below 10 C on the MVA, 83% were successfully resuscitated. None of the dogs maintained for two hours below 10 C without circulation could be resuscitated. Eleven dogs were studied for a long-term survival after chest closure. Only four of them survived longer than three days. Death after rewarming was due to severe pulmonary insufficiency. Results of this study suggest that provision of oxygenation and a pulsatile circulation during hypothermia improve tissue viability of nonhibernators. The model shows potential for in situ preservation of multiple organs in the cadaver.
A rabbit ear model of the human digit was utilized to determine the vascular response to peripheral sympathectomy. Vascular responses were evaluated by subjecting chronically instrumented rabbits to a cold stress before and after sympathectomy surgery. The typical response to cold stress is for ear temperatures and auricular cutaneous perfusion to decrease during the cooling phase of the test and to increase toward baseline levels during the rewarming phase after cold exposure. Following peripheral sympathectomy, ear temperatures were significantly increased during both the cooling and rewarming phase of the cold stress test although overall ear perfusion and skin perfusion were not different from sham-operated rabbits. The responses observed in the rabbit ear following peripheral sympathectomy appear to mimic those noted in patients receiving digital peripheral sympathectomies for the treatment of refractory pain and ulceration. Peripheral sympathectomy may result in clinical improvements in patients because it improves both total digital and nutritional cutaneous blood flow. Peripheral sympathectomy in normal rabbit ears does not result in altered perfusion patterns with cold exposure although ear temperature is significantly higher. This pattern of changes suggests that the distribution of extremity perfusion is altered even though overall extremity perfusion and cutaneous perfusion per se are not significantly different from sham-operated controls. Complete sympathectomy was accompanied by a persistent increase in ear temperature and a dissociation between conductance and microvascular perfusion. Auricular conductance was transiently increased and then decreased to levels below preoperative control values. Microvascular perfusion is decreased immediately following amputation/replantation and thereafter increases.
Damage sustained by an ischaemic kidney is reduced by cooling the organ. For this reason kidneys are rapidly cooled during the retrieval operation and preserved at low temperature before implantation. When the kidney is removed from cold storage for implantation into the recipient it gradually rewarms (second warm ischaemic time) and a prolonged second warm ischaemic time has been shown to be a cause of acute tubular necrosis following transplantation. The temperature rise in a kidney during implantation has been poorly investigated and little work to minimize that rise has been carried out. This study investigates, in an animal model, the changes that occur in the core temperature of kidneys during the second warm ischaemic time. A jacket has been designed which greatly reduces the rate of kidney rewarming during simulated operative conditions. Kidneys unprotected by the test system showed a rapid rise in temperature from a mean of 1 degrees C to a mean of 20 degrees C after 45 min, compared with those kidneys placed in the protective jacket in which the temperature rose to a mean of only 8 degrees C in the same time. The jacket is not bulky and is simple to use. Maintaining a low kidney core temperature during the second warm ischaemic time will reduce injury to the kidney and should be part of routine clinical practice.
An apparatus was devised which utilizes local cooling to reversibly interrupt the axonal transport of dopamine-beta-hydroxylase (DBH) in rabbit sciatic nerves in vitro. Lowering the temperature of a short region of nerve to between 1 and 3 degrees C, while keeping the remainder at 37 degrees C, caused DBH activity to accumulate in and proximal to the cooled region. This accumulation was evident after 0.5 hr of cooling and increased in a nearly linear fashion with time for about 3 hr. The cooling-induced interruption in transport was rapidly reversed when nerves were rewarmed to 37 degrees C. Upon rewarming after local cooling for 1.5 hr, a peak of accumulated DBH activity migrated toward the distal end of the nerve at a velocity of 300 +/- 17 mm/day. This velocity was maintained for as long as the peak could be followed and was four times greater than the average velocity estimated from the rate of accumulation of DBH activity above a ligature at the distal end of these same nerves. It is concluded that ligation experiments grossly underestimate the true velocity of axonal transport of DBH and that the present technique offers great advantages in permitting direct study of the migration of separate axonal compartments of transported materials.
In order to elucidate the role of superoxide dismutase (SOD on ischemia-reperfusion injury, bovine and porcine aortic endothelial cells were transfected with retroviral vector LSODRNL containing human Cu,Zn-SOD cDNA and their SOD activities were evaluated by measuring superoxide scavenging capability. Successful augmentation of Cu,Zn-SOD up to 2.7-fold in bovine and 1.9-fold in porcine cells was obtained. After 24 h cold preservation followed by 4 h rewarming, cell viability compared with that of pre-preservation was significantly increased in both types of cells (P < 0.01). Moreover, after exposure to superoxide, viability of the porcine cells with high SOD activity was significantly improved compared to control cells. We consider that transfection of human Cu,Zn-SOD cDNA to arterial endothelial cells is useful for preventing from cold preservation-rewarming or ischemia-reperfusion injury.
Head plasma membranes were isolated from fresh or cryopreserved ejaculated boar spermatozoa and the lipids were extracted for determination of lipid fluidity (n = 6 for fresh and cryopreserved) and for compositional analysis (n = 5 for fresh, 6 for cryopreserved). Composition of the egg yolk extender was also determined. For fluidity determination, the mixed lipids were allowed to form natural liposomes. Bilayer fluidity of these liposomes was analyzed in the presence or the absence of 1 mM Ca2+ with the probes tPNA, which preferentially locates into gel-phase areas, and cPNA, which enters fluid and gel-phase areas equally and thus assesses bulk lipids. Fluidity of liposomes declined significantly during controlled-rate cooling for all samples. Compared to lipids from fresh membranes, gel lipids from cryopreserved cells lost fluidity at a significantly more rapid rate, as did bulk lipids in the presence of Ca2+ (P < 0.001). Fluidity increased during subsequent rewarming (5 to 50 degrees C), again at a slower rate for lipids from fresh cells, with the cryopreservation effect being significant for all probe/Ca2+ combinations (P < or = 0.05). Calcium altered the fluidity characteristics of membrane lipids from fresh but not cryopreserved sperm when analyzed during cooling with cPNA (P < 0.01) and during rewarming with cPNA (P < 0.0001) and tPNA (P < 0.05). Lipids from cryopreserved cells contained significantly less sphingomyelin (14.6 +/- 1.1 vs 22.4 +/- 1.6 mol%) and more phosphatidylcholine (51.5 +/- 2.0 vs 40.5 +/- 2.4%). The octadecanoate (18:0) content in both phosphatidylserine and phosphatidylethanolamine decreased after cryopreservation (P < 0.05). The polyunsaturated fatty acids docosatetraenoate (22:4) and/or arachidonate (20:4) increased in these phospholipids and in sphingomyelin and phosphatidylinositol (P < 0.05). The alterations in the molecular interactions, composition, and Ca2+ sensitivity of membrane lipids may interfere with the normal membrane events of fertilization.
We tested the tolerance of human corneas to a vitrification solution, modified VS41A, containing 3.1 M dimethyl sulfoxide, 3.1 M formamide, and 2.2 M 1,2-propanediol in a carrier solution consisting of the corneal storage medium CPTES with 2.5% w/v chondroitin sulfate. Seven human corneas were exposed for 10 min each to graded concentrations of the solution at 0 degree C, remaining in the full-strength solution for 10 min. The corneas had significantly more endothelial cell damage (P < 0.05) than seven mated control corneas, but it was minimal (4.3% cell loss). Attempts at vitrification and rewarming of three corneas exposed to the solution by this protocol, however, resulted in ice formation in the peripheral corneal stroma and severe endothelial damage. Presumably, equilibration with the cryoprotectant in the thicker periphery of the human cornea had not occurred. Ice did not form on the center of one cornea, and substantial numbers of central endothelial cells survived after vitrification in this case. Immersion of the human corneas for 25 min in each of the four graded solutions at 0 degree C was required for sufficient penetration of the cryoprotectant to allow total corneal vitrification and rewarming without ice formation. This prolonged exposure to modified VS41A caused unacceptable damage to the corneal endothelium, however. Successful vitrification of human corneas with this solution will require a safe method for obtaining corneal equilibration with the cryoprotectant.
Myocardial dysfunction after hypothermic protection has been linked to various mechanisms. Coronary vasospasm in particular may be responsible for ischemic injury during reperfusion. Herein we hypothesized that coronary arteries (CA) sustain a cold-induced contraction during hypothermia mediated by a protein tyrosine kinase (PTK)-/protein tyrosine phosphatase (PTP)-dependent pathway. Isolated newborn lamb CA rings were studied in a tissue bath for isometric contraction during 2-h profound (17 degrees C) or ultra-profound (7 degrees C) hypothermia. In parallel, protein tyrosine phosphorylation was evaluated by use of the Western blot technique. Na-orthovanadate (SOV) and genestein (GEN) were used separately and in combination to evaluate the effect of PTK/PTP activation on CA contraction and tyrosine phosphorylation during cooling (17 or 7 degrees C) vs 37 degrees C. Cooling from 37 to 7 degrees C induced transient contraction at approximately 17 degrees C (29% KCl response), which was more prominent during rewarming to 37 degrees C (36% KCl). Cooling to 17 degrees C resulted in sustained contraction (7-10% KCl), which was reversible upon rewarming. Cold-induced contraction was significantly enhanced by SOV (7- to 10-fold at 17 degrees C; 2-fold at 7 degrees C) and abolished by GEN. Concurrently, tyrosine phosphorylation of 33-, 45-, and 104-kDa proteins increased during cooling (35-100% at 17 degrees C; 46-66% at 7 degrees C). Tyrosine phosphorylation was similarly enhanced by SOV (1.7- to 2.3-fold at 17 degrees C; 2.9- to 3.9-fold at 7 degrees C) and abolished by GEN in the presence or absence of SOV. These results support a prominent role for the PTK/PTP signal transduction pathway in the coronary artery cold-induced contraction. This information provides one possible biomolecular mechanism linked to ischemia/reperfusion pathophysiology of CA in neonatal hearts exposed to hypothermic myocardial protection.
We very recently showed (using a blood-free perfusion model) that cold preservation sensitized rat hepatocyte functions to rewarming ischemic injury and that the injury can be prevented by repleting high-energy adenylates in the liver by short-term oxygenated warm reperfusion. Here we investigated whether short-term reperfusion after the preservation period can improve hepatic graft function in a blood reperfusion model. Eighteen-hour cold-preserved rat livers either untreated (Group A) or pretreated by 30-min oxygenated warm reperfusion after preservation (Group B) were subjected to 20-min ischemic rewarming and then reperfused with blood. Livers in Group B compared to Group A exhibited approx. three times increased bile production and bromosulfophthalein excretion, nearly 7-fold decreased swelling, and 1.2-fold improved blood flow. These results suggest that repletion of the energy by short-term oxygenated reperfusion after prolonged preservation may improve markedly initial hepatic graft function.
This study investigated the effects of normothermic cardiopulmonary bypass (CPB) and circulatory arrest (DHCA) on expression of specific genes in neonatal piglet brain. CPB was performed through the chest at 100 ml/kg/min for 2 hrs at 37 degrees C. In the second group of animals, CPB was begun as described above and then animals were cooled to a nasopharyngeal/brain temperature of 18 degrees C. When the brain temperature reached 18 degrees C, the CPB circuit was turned off. After 60 min of circulatory arrest (DHCA), CPB was resumed at 100 ml/kg/min, and the piglets were rewarmed to a temperature of 36 degrees C. In both groups, the animals remain sedated, paralyzed, mechanically ventilated, and continuously monitored throughout a four hour study period after CPB. Oxygen pressure in the microvasculature of the cortex was measured by oxygen dependent quenching of phosphorescence. The aRNA technique was used to assess mRNA steady-state levels in the brain tissue. Control oxygen pressure (pre-bypass) was 61 +/- 5 Torr and during CPB this decreased to 32 +/- 7 Torr on the beginning of bypass and to 36 +/- 5 Torr at the end of bypass. During the recovery period, cortical oxygenation steadily decreased, reaching 29 +/- 8 Torr at the end of the four hours period. Cortical oxygen decreased during DHCA to near zero and during rewarming and recovery increased to 35 +/- 6 Torr. Measurements of gene expression following CPB revealed significantly increased levels of mRNA for NMDAR1, DARPP-32, CamKII, GluR1, and D1AR. DHCA caused changes similar to those for CPB in levels of mRNA for NMDAR1, DARPP-32, CamKII and GluR1. In contrast, DHCA caused significantly increased levels of mRNA for GluR6 and GABRB1. There was no significant alteration in the level of D1AR following DHCA. The results showed that DHCA caused much larger alterations in gene expression in the critical metabolic signaling pathways tested than did CPB.
Quantitative measurements of oxygen distribution in the microcirculation of the brain cortex of newborn piglets were made during different modes of cardiopulmonary bypass. Three groups of animals, anesthetized and mechanically ventilated, were studied. The first group of animals were maintained on normothermic cardiopulmonary bypass (CPB) at a flow of 100 ml/kg/min, while the second and third groups underwent low flow hypothermic cardiopulmonary bypass (40 ml/kg/min at 18 degrees C) (LFCPB) and deep hypothermic (18 degrees C) circulatory arrest (DHCA), respectively. After bypass, the piglets were monitored for a two hours post-bypass recovery period. CPB caused a decrease in the cortical oxygen from 62 +/- 3 mm Hg to 32 +/- 7 mm Hg at the beginning of bypass and to 36 +/- 5 mm Hg at the end of bypass. During the recovery period, cortical oxygenation steadily decreased, reaching 29 +/- 8 mm Hg at the end of the experiment. With initiation of LFCPB, cortical oxygen decreased to 22 +/- 7 mm Hg. Upon rewarming cortical oxygen increased to 37 +/- 5 mm Hg and then decreased again to about 30 mm Hg at the end of two hours of post-bypass recovery. Similar changes in cortical oxygenation were observed during DHCA. In DHCA cortical oxygen decreased to 19 +/- 4 mm Hg and during rewarming and recovery increased to 35 +/- 6 mm Hg. In conclusion, it has been shown that in newborn piglets recovering from CPB, LFCPB and DHCA, when the blood pressure remained above 55 mm Hg and therefore total blood flow should be well maintained, oxygen pressure in the microvasculature is significantly lower than for pre-bypass. It is suggested that the decreased oxygenation is due to increased heterogeneity in resistance in the microcirculatory units, resulting in broadened distribution of flow rates and oxygen levels.
The present study investigates the neuroprotective effects of temporary mild systemic hypothermia and selective brain cooling against focal cerebral infarction in the rat and the changes of cortical blood flow, and compares these two treatment modalities. In permanent middle cerebral artery (MCA) model, the treatments were induced 15 min following the artery occlusion. The animals were kept at the desired rectal or brain temperature (about 32 degrees C) for 30 min; (each, n = 6) and for 1 hr (each, n = 6), and then allowed to rewarm spontaneously, whereas control animals were kept at normothermia throughout the experiment. The volumes of brain infarction and edema were assessed 24 hr post-occlusion. The blood flow of the dorsolateral cortex was monitored by Laser-Doppler flowmetry (LDF) in the other experiments. Hemispheric infarct volume was attenuated only in the animals treated for 1 hr with systemic hypothermia (49.2%, P < 0.001) and selective brain cooling (26.7%, P < 0.01). The volume of brain swelling was diminished only in the animals treated with systemic hypothermia for 1 hr (23.6%, P < 0.05). LDF examination revealed a sharp drop in blood flow upon MCA occlusion and maintaining in low blood flow throughout the experiment in the control and systemic hypothermia. However, in the selective brain cooling, the reduced blood flow increased from 40% to 70% of baseline value while the brain was rewarmed. The present study indicates that mild systemic hypothermia has much stronger protective effects against focal cerebral infarction and edema than selective brain cooling. The lack of protective effects of selective brain cooling may be caused by post-cooling cerebral hyperemia in the ischemia area.
Raynaud's syndrome (RS) is characterized by intense blood vessel spasm resulting in finger blanching. Treatment primarily involves vasodilation. Thromboxane A2 (TXA2) has been shown to be a potent vasoconstrictor and platelet aggregant. It may be possible to produce a vasodilatory and anti-thrombotic effect by blockade of the TXA2 receptors. ICI 192,605 is a potent TXA2 receptor antagonist and we studied its effects on platelet aggregation and digital blood flow in patients with RS. Sixteen patients with RS completed this double-blind, randomized, placebo controlled study. Each patient was seen on three separate occasions and was given ICI 192,605 (100 mg orally) on one occasion and matching placebo tablets on the other two. We measured platelet aggregation using platelet rich plasma (PRP) stimulated by U46619, a thromboxane (TX) mimetic. The concentration of U46619 required to cause just over 50% platelet aggregation before the administration of either ICI 192,605 or placebo (pre-dose) was noted. The same concentration of U46619 was used to stimulate the PRP sample at 1 h after the administration of ICI 192,605 or placebo (post-dose) and the percentage of platelet aggregation was again noted. Fingertip skin blood flow was also measured 1.25 h post-dose using a laser Doppler flowmeter. Patients were seated in a temperature controlled chamber which was initially heated to 40 degrees C to induce centrally mediated vasodilatation. The temperature was then lowered to 12 degrees C followed by rewarming to 40 degrees C. Steady blood flow values at these temperatures were measured and the rates of cooling and rewarming were also noted.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the significance of N-acetyl-beta-glucosaminidase (beta-NAG) and type III procollagen peptide (P-III-P) in the effluent of rodent hepatic grafts. After total hepatectomy, the livers were preserved in chilled, lactated Ringer's solution and then divided into five groups (n = 10 each): group 1, 4 h preservation only; group 2, 4 h preservation and rewarming; group 3, 6 h preservation only; group 4, 6 h preservation and rewarming; and group 5, minimal preservation only. The beta-NAG of groups 2 and 4 was significantly higher than that of groups 1 and 3 (0.98 +/- 0.5 U/l vs 0.21 +/- 0.12 U/l; P < or = 0.01 and 1.76 +/- 0.67 U/l vs 0.38 +/- 0.25 U/l, respectively; P < or = 0.01), while that of group 4 was significantly higher than that of group 2 (1.76 +/- 0.67 U/l vs 0.98 +/- 0.50 U/l; P < or = 0.05). The P-III-P of group 4 was significantly higher than that of group 2 (0.133 +/- 0.008 U/ml vs 0.110 +/- 0.015 U/ml; P < 0.01). We conclude that beta-NAG is a novel parameter of parenchymal and nonparenchymal cells, while P-III-P reflects the integrity of the hepatic sinusoidal extracellular matrix.