Comparison of neurological outcomes following witnessed out-of-hospital ventricular fibrillation defibrillated with either biphasic or monophasic automated external defibrillators.

BACKGROUND: Biphasic waveform defibrillation results in higher rates of termination of fibrillation than monophasic waveform defibrillation but has not been shown to improve survival outcomes. OBJECTIVE: To compare the effectiveness of a biphasic automated external defibrillator (AED) with a monophasic AED for witnessed out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF). METHODS: In a prospective population-based cohort study, adults with witnessed VF OHCA were treated with either monophasic or biphasic waveform AED shocks. The primary outcome measure was neurologically favourable 1-month survival, defined as a Cerebral Performance Categories score of 1 or 2. RESULTS: Of 366 adults with witnessed OHCA of presumed cardiac aetiology, 74 (20%) had VF. Termination of VF with the first shock tended to occur more frequently after biphasic AED shocks (36/44 (82%) vs 20/30 (67%), p = 0.14). Return of spontaneous circulation (ROSC) occurred more frequently after biphasic AED shocks (29/44 (66%) vs 8/30 (27%), p = 0.001). Neurologically favourable 1-month survival was also more frequent in the biphasic group (10/44 (23%) vs 1/30 (3%), p = 0.04). The median time interval from the first shock to the second shock was 67 s in the monophasic group and 24 s in the biphasic group (p = 0.001). CONCLUSIONS: Treatment with biphasic AED shocks improved the likelihood of ROSC and neurologically favourable 1-month survival after witnessed VF compared with monophasic AED shocks. In addition to waveform differences, a shorter time interval from the first shock to the second shock could account for the better outcomes with biphasic AED.

Delayed hemispheric neuronal loss in severely head-injured patients.

Recent experimental studies have revealed that traumatic brain injury as well as ischemic brain injury can cause chronic progressive neuronal damage. In the present study, we demonstrate previously unreported delayed cerebral atrophy on computerized tomography (CT) scans in severely head-injured patients. Seventeen severely head-injured patients who required mild hypothermia to control intracranial hypertension after the failure of conventional therapies were retrospectively analyzed. All 17 patients survived more than 1 year. Delayed neuronal loss (DNL) was observed in only eight of the 17 patients. Eight patients with DNL required longer durations of mild hypothermia to control intracranial hypertension than nine patients without DNL. Six of these eight patients with DNL achieved functional recovery despite progressive atrophic changes demonstrated on CT scans. On CT scans, DNL was characterized by (1) the sudden appearance at several months postinjury of a low-density area in the hemisphere ipsilateral to the injury; (2) the preservation of essential cortical structure although related white matter structures showed severe atrophic changes; and (3) no spread of the low-density area to the contiguous territory of the other main cerebral artery. It is concluded that focal primary injury to underlying brain, if severe enough, can result in delayed hemispheric atrophy.

Effect of 3-hydroxybutyrate on posttraumatic metabolism in man.

Of 20 patients suffering trauma, with Injury Severity Scores greater than 20, 11 patients received DL-3-hydroxybutyrate (3-OHB) at a rate of 25 mumol/kg/min for 3 hours. The remaining nine patients received sodium DL-lactate at the same rate as the control subjects. With increased arterial concentrations of ketone bodies, the femoral arteriovenous difference (arterial concentration minus venous concentration) of ketone bodies increased proportionally in the 3-OHB group (R = 0.853, p less than 0.001). Venous concentrations of nonesterified free fatty acids, alanine, glycine, and valine were decreased significantly in the 3-OHB group as compared to the control group. The concentration difference between femoral vein and artery (venous concentration minus arterial concentration) for these substrates also decreased, indicating decreased release from the extremity. A decrease in venous concentration of alanine and difference between femoral vein and artery reached 102.3 +/- 69.3 mumol/L and 32.6 +/- 22.8 mumol/L (mean +/- SD), respectively, after 3-OHB infusion. Decreased alanine release from muscle during 3-OHB infusion in traumatized patients suggests a suppressive effect of ketone body on posttraumatic protein catabolism.

Paradoxical positive nitrogen balance in burn patients receiving high-dose administration of insulin for nutritional care.

BACKGROUND: Nitrogen balance in patients who need high-dose administration of insulin has not been evaluated clinically. The purpose of this study was to compare the difference in nitrogen balance between burn patients who received high-dose administration of insulin and those who did not. METHODS: This study was performed in 19 severely burned adults with no liver or kidney failure. Patients were divided into two groups on the basis of the mean ratio of administered insulin and calorie intake (I/C) for the initial 4 weeks, a high I/C group (n = 9) and a low I/C group (n = 10). There were no significant differences between the two groups regarding age, percentage of area burned, and body weight. Nitrogen balance, blood urea nitrogen, and urine urea nitrogen were measured in all patients. Plasma concentrations of glucose, insulin, glucagon, cortisol, and urinary excretion of 3-methyl-histidine were measured in 12 patients (six in each group). RESULTS: Until day 10 both groups exhibited similar changes in plasma concentrations of glucose, insulin, glucagon, and cortisol. Subsequently, plasma concentrations of insulin and glucagon began to decrease in the low I/C group, whereas a high level was sustained in the high I/C group (p < 0.05). Plasma glucose and cortisol measurements showed no significant differences between the two groups. Blood urea nitrogen levels and urinary excretion of 3-methyl-histidine were not different between the two groups. Urine urea nitrogen excretion in the high I/C group, however, was significantly lower than that in the low I/C group from day 8 (p < 0.05). Thus the high I/C group achieved positive nitrogen balance more quickly than the low I/C group. Paradoxically, however, the high I/C group was at higher risk of septic complications and exhibited higher mortality than the low I/C group (p < 0.05). CONCLUSIONS: These results indicate that an improvement in nitrogen balance, which is accepted as a good thing in the management of critically ill patients, is not necessarily good in the high I/C group and that residual nitrogen was retained within the body in the high I/C group.

Low oxygen extraction despite high oxygen delivery causes low oxygen consumption in patients with burns recovering slowly from operative hypothermia.

BACKGROUND: Patients with burns who eventually succumbed to their injuries tended to recover more slowly from operative hypothermia than those who survived. Slower recovery was associated with a lower postoperative oxygen consumption (VO2). We have now investigated whether this was due to impairment of oxygen delivery or extraction. METHODS: This study was performed in 13 adult patients with severely burns. One hundred four measurements of VO2 by indirect calorimetry were made during recovery from 23 episodes of operative hypothermia in 11 patients. Sixty-six measurements of oxygen transport variables by balloon-tipped pulmonary artery catheter were made after 17 episodes of operative hypothermia in six patients. Body temperature was monitored in the urinary bladder. RESULTS: The rate of temperature rise (T) showed a strong positive correlation with VO2 measured both by indirect calorimetry (r = 0.91, p < 0.001) and by balloon-tipped pulmonary artery catheter (r = 0.83, p < 0.001). Oxygen delivery (DO2) was above normal in nearly all patients. Oxygen extraction was low in patients recovering slowly (T < 1.0 degree C/hr) and high in those recovering quickly (T > or = 1.0 degree C/hr). During fast recovery VO2 (373 +/- 77 ml.min-1.m-2; mean +/- SD) was approximately three times normal and was independent of DO2. In contrast, a strong linear relationship existed between VO2 and DO2 during slow recovery (r = 0.76, p < 0.001). CONCLUSIONS: Patients with burns with slow recovery from operative hypothermia exhibited impaired oxygen extraction and dependence of VO2 on DO2 over a wide range. This picture resembles that in patients with critical illness.

IgE-mediated drug fever due to histamine H2-receptor blockers.

Drug-induced fever due to histamine H2-receptor blockers was experienced by a 55-year-old man. The patient became febrile 5 days after receiving cimetidine, and continued to be febrile until the drug was stopped. His maximum body temperature was above 40 degrees C. Challenge tests with cimetidine and ranitidine showed that the fever was caused by the H2-blocker. The patient's serum IgE concentration increased markedly to 2590 IU/ml 10 days after admission, and skin tests for cimetidine and ranitidine were positive. Lymphocyte stimulation tests were positive for both drugs (stimulation indices: 193% for cimetidine and 325% for ranitidine). Cimetidine-induced fever has generally been thought to be due to a direct effect on the thermoregulatory centre in the hypothalamus, on the basis of experimental studies of the injection of cimetidine to the cerebral ventricles. However, clinical evidence has not excluded an allergic involvement in this type of drug-induced fever. This patient's fever was proven to be due to administration of the H2-blocker, and the mechanism of action was IgE-mediated.

Selection of severely head injured patients for mild hypothermia therapy.

OBJECT: The authors have analyzed the efficacy of inducing mild hypothermia (34 degrees C) in 62 severely head injured patients to control fulminant intracranial hypertension. METHODS: All 62 patients fulfilled the following criteria: 1)persistent intracranial pressure (ICP) greater than 20 mm Hg despite fluid restriction, hyperventilation, and high-dose barbiturate therapy; 2) an ICP lower than the mean arterial pressure; and 3) a Glasgow Coma Scale (GCS) score of 8 or less on admission. The patients were divided into three groups based on computerized tomography findings: extracerebral hematoma (34 patients with subdural and/or epidural hematoma), focal cerebral lesion (20 patients with localized brain contusion and/or intracerebral hematoma), and diffuse swelling (eight patients with no focal mass lesion). Mild hypothermia prevented ICP elevation in 35 (56.5%) of the 62 patients whose ICP was greater than 20 mm Hg despite conventional therapies. Among those 35 patients whose ICP was controlled by mild hypothermia, 12 (34.3%) achieved functional recovery (good outcome or moderate disability). However, functional recovery was observed in only five (10.9%) of the 46 patients whose ICP was greater than 40 mm Hg after conventional therapies. Of 40 patients with an admission GCS score of 5 to 8, there were 11 (27.5%) who achieved functional recovery. On the contrary, mild hypothermia was not effective in 22 patients with an admission GCS score of 3 or 4. In the patients with focal cerebral lesions, ICP was controlled by mild hypothermia in 17 patients (85%) and patient outcome was intimately related to the extent of the damage. Among 18 patients with extracerebral hematoma who had a midline shift of 9 to 12 mm, raised ICP could be successfully controlled by mild hypothermia in 16 patients (88.9%) and three (16.7%) achieved functional recovery. However, ICP could not be controlled in patients with extracerebral hematoma who had a midline shift of 13 mm or more. In patients with diffuse swelling, ICP elevation could not be prevented at all by mild hypothermia. CONCLUSIONS: The authors conclude that mild hypothermia is effective for preventing ICP elevation in patients without diffuse brain swelling in whom ICP remains higher than 20 mm Hg but less than 40 mm Hg after conventional therapies.

Recovery from postoperative hypothermia predicts survival in extensively burned patients.

To clarify the cause of postoperative hypothermia in extensively burned patients, factors affecting postoperative hypothermia were studied in 16 extensively burned adult patients (8 survivors and 8 nonsurvivors) with a burn index greater than 35. Body temperature was monitored continuously in either the urinary bladder or rectum. Hypothermia of less than 35 degrees C occurred in 89% (66 of 74) of the total operations performed in these 16 patients. The rate of temperature rise (RTR) was significantly lower in nonsurvivors (0.4 +/- 0.2 degrees C/h) than in survivors (1.7 +/- 0.9 degrees C/h; p < 0.001). Continuous indirect calorimetry performed in seven patients (four survivors and three nonsurvivors) demonstrated that RTR was determined primarily by heat production. The measured energy expenditure reached only 1.7 +/- 0.2 times the basal energy expenditure during rewarming in nonsurvivors, whereas it was 2.7 +/- 0.9 times the basal energy expenditure in survivors (p < 0.01). Surprisingly, in nonsurvivors, the RTR was significantly decreased even during the first 2 weeks. These findings suggest that those who cannot generate heat well in postoperative hypothermia are unable to produce the additional energy required to overcome sepsis.

Effect of ketone bodies on hyperglycemia and lactic acidemia in hemorrhagic stress.

BACKGROUND: To investigate the effect of hyperketonemia on altered glucose metabolism under stress conditions, we infused sodium D-3-hydroxybutyrate (3-OHB) into rats in hemorrhagic hypotension and evaluated the plasma concentration of substrates related to glucose metabolism. METHODS: Three groups of anesthetized rats (weight, 280 g to 320 g) were bled acutely, and their mean arterial pressures were maintained at 40 mm Hg. From 1 hour before hemorrhage to the end of the experiment, rats in the first group (n = 10) were infused with 3-OHB at a rate of 30 mumol/kg.min (3-OHB group), those in the second group (n = 10) received glucose and sodium bicarbonate (glucose group), and the remaining 10 rats received only sodium bicarbonate and no energy substrates (control group). Sodium bicarbonate was used to control the alkalizing effect of 3-OHB. RESULTS: Hyperketonemia (1158 +/- 30 mumol/L - 1618 +/- 154 mumol/L) occurred only in the 3-OHB group. Hyperglycemia and lactic acidemia during hemorrhagic shock were suppressed significantly compared with the control group. Plasma concentration of alanine was also lower compared with the control group. In the glucose group, although plasma lactate concentration was lower, plasma glucose concentration was not suppressed, and plasma alanine concentration was higher in comparison with the control group during hemorrhagic shock. There was no significant difference in plasma insulin concentration among the three groups. CONCLUSIONS: These results suggest that administered 3-OHB may suppress glycolysis during hemorrhagic shock.

The dimer and trimer of 3-hydroxybutyrate oligomer as a precursor of ketone bodies for nutritional care.

BACKGROUND: Ketone bodies have been considered as a means of providing energy because of their good penetration and rapid diffusion in peripheral tissues. However, because the currently available form of 3-hydroxybu-tyrate is the sodium salt, the sodium load is problematic. To avoid it, a mixture of dimer and trimer has been prepared as a precursor of D-3-hydroxybutyrate. The purpose of this study was to investigate whether and how the solution would be converted to monomers. METHODS: The plasma concentration of 3-hydroxybutyrate monomer was measured in 10 rats during infusion of dimer and trimer. Stepwise dilutions of the solution were incubated with serum and liver homogenates from five rats, serum samples from five volunteers, and a liver sample from one patient with liver injury. The solution also was incubated with carboxylesterase and triacylglycerol lipase. The concentration of monomer in the medium was measured after incubation. RESULTS: The plasma concentration of 3-hydroxybutyrate monomer reached 572 +/- 11 micromol/L 15 minutes after beginning infusion of the mixture at a rate of 25 micromol x kg(-1) x min(-1) and 270 +/- 40 micromol/L at a rate of 12.5 micromol x kg(-1) min(-1). The solution was converted completely to monomers when incubated with rat serum or liver homogenate for 10 minutes. The mixture also was hydrolyzed by human liver homogenate but not by serum. CONCLUSIONS: The dimer and trimer of 3-hydroxybutyrate can be converted rapidly to monomer in rat and human tissues. 3-Hydroxybutyrate oligomers could be an energy substrate for injured patients.

Effects of concentration reduction and partial replacement of paraquat by diquat on human toxicity: a clinical survey.

Paraquat poisoning was studied in 174 patients over a 12-month period when a new, low concentration paraquat product (4.5% w/v paraquat ion mixed with 4.5% w/v diquat ion; 63 cases) replaced the original high concentration paraquat product (20% w/v paraquat ion only; 111 cases). In both groups approximately 60% of the patients died from circulatory failure accompanied by multiple organ failure within a week of ingesting the products. However, a remarkable reduction in late deaths from respiratory failure was noted in the new product group (17.1% vs 6.3%). This was reflected in this group's improved survival (23.4% vs 34.9%). The improvement in survival seems to be attributable to the dilution of paraquat with diquat which seems to have a different toxicological profile to paraquat.

[A case of sudden onset of toxic cholangitis].

A previously healthy 43-year-old male was admitted to the hospital because of the impared consciousness. Although a passage of the bile duct was good, the patient was in severe biliary sepsis and cardiac arrest occurred repeatedly. Plasma concentration of TNF increased markedly suggesting a pathogenic role of TNF in the course of the patient. Plasma exchange was effective for hemodynamic stabilization. Recent advances in treatment of acute cholangitis has been brought by early drainage of the obstruction in the bile duct using endoscopic or percutaneous drainage. However this case suggests that only drainage of the infection focus is not sufficient for the life saving in such a patient and other therapeutic approach such as an inactivation of TNF activity should be considered.

[A case report of pseudoxanthoma elasticum with upper gastrointestinal hemorrhage].

A gastric hemorrhage in a patient with pseudoxanthoma elasticum (PXE) is reported. A 44-year-old woman was admitted to our hospital with hematemesis. Bleeding point was located at upper body of the stomach. As neither endoscopic alcohol injection nor operative hemostasis by over sewing under gastrotomy were unsuccessful, total gastrectomy was performed. Histologic examination of the stomach revealed fragmentation of elastic fiber in the internal lamina of arteriole and degeneration of muscle layer. This change was observed fundamentally in all specimens obtained from different region of the stomach. In addition to describing clinical and pathological feature of this case, the management of gastric hemorrhage in patients with PXE is discussed.

Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death-1 on the growth of established tumors.

Interferon-alpha (IFN-α) has strong antitumor effects, and IFN-α gene therapy has been used clinically against some cancers. In this study, we evaluated the efficacy of the combination of IFN-α-transduced tumor cell vaccines and programmed cell death 1 (PD-1) blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-α. In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Analyses of immunohistochemistry and tumor-specific lysis were performed. The outgrowth of the established tumors was significantly reduced in mice treated with the combination of IFN-α and anti-PD-1. Immunohistochemical analyses of the therapeutic model showed marked infiltration of CD4(+) cells and CD8(+) cells in the established MC38 tumors of mice treated with both IFN-α and anti-PD-1. Significant tumor-specific cytolysis was detected when splenocytes of mice that were treated with both IFN-α and anti-PD-1 were used as effector cells. These results suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-α. The combination of IFN-α gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials.

Dendritic cell therapy with interferon-alpha synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model.

Both dendritic cell (DC)-based immunotherapy and interferon (IFN)-alpha therapy have been proved to have potent long-lasting antitumor effects. In anticipation of synergistic antitumor effects, we performed combination therapy with DCs and IFN-alpha gene-transduced murine colorectal cancer MC38 cells (MC38-IFN-alpha). DCs incubated with MC38-IFN-alpha, but not neomycin-resistance gene-transduced MC38 cells (MC38-Neo), effectively enhanced proliferation of allogeneic splenocytes in vitro. In 12 of 17 mice, DCs in combination with MC38-IFN-alpha prevented the development of a parental tumor, while DCs and MC38-Neo did in only three of 17 mice (P=0.008). In a therapeutic model of an established parental tumor, inoculation of DCs and MC38-IFN-alpha suppressed the growth of the established parental tumors significantly compared with the administration of DCs with MC38-Neo or naive splenocytes with MC38-IFN-alpha (P=0.016 and 0.024, respectively). Analyses of immunohistochemistry and tumor-infiltrating mononuclear cells showed that CD8(+), CD11c(+), and NK1.1(+) cells markedly infiltrated the established tumors of mice treated with DCs and MC38-IFN-alpha. From the results of observation of parental tumor outgrowth in immune cell-depleted mice, CD8(+) cells, and asialo-GM-1(+) cells were thought to contribute to the antitumor effects induced by the combination therapy. Furthermore, MC38-specific cytolysis was detected when splenocytes of mice inoculated with DCs and MC38-IFN-alpha cells were stimulated with MC38-IFN-alpha cells in vitro. Since DC-based immunotherapy in combination with IFN-alpha-expressing tumor cells induces potent antitumor cellular immune responses, it should be considered for clinical application.

Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-alpha transduction.

To investigate antitumor mechanisms in interleukin (IL)-4 therapy, we established an IL-4-overexpressing MC38 murine colorectal cancer cell line (MC38-IL4). As a therapy against established tumors, MC38-IL4 cells were inoculated contralaterally 7 days after wild-type (MC38-WT) cells had been injected, significantly reducing growth of wild-type tumors (P=0.030). Immunohistochemical analysis showed numerous granulocytes infiltrating wild-type tumors of MC38-IL4-inoculated mice. Injection of MC38-IL4 cells in leukocyte-depleted mice confirmed that granulocytes were involved in IL-4-related primary antitumor effects. Inoculation of MC38-WT in leukocyte-depleted mice initially injected with MC38-IL4 suggested that T cells contributed to the antitumor effects. To investigate tumor-specific responses, we stimulated splenocytes of MC38-immune mice with MC38-IL4 cells in vitro, resulting in MC38-specific lysis (57.5+/-7.2%, effector to target ratio=20). Treatment of established wild-type tumors with MC38-IL4 in combination with interferon (IFN)-alpha-overexpressing MC38 cells (MC38-IFNalpha) significantly reduced the growth of wild-type tumors (P=0.009). In vitro IFN-gamma production by splenocytes from mice injected with both MC38-IL4 and -IFNalpha was greatly enhanced in comparison with MC38-IL4 alone, while IL-10 production was not increased. Thus, granulocytes concern early antitumor effects of IL-4 therapy. Subsequently, IL-4 induces long-lasting, tumor-specific immune responses. IL-4 appears to promote a T-helper 1-type antitumor immune response, which is enhanced in cooperation with IFN-alpha.

Bradycardia and hypotension associated with severe hemorrhage are reversed by morphine given centrally or peripherally in anesthetized rats.

BACKGROUND: Severe simple hemorrhage (blood loss in the absence of tissue damage and nociception) leads to a reflex bradycardia and hypotension. Earlier studies showed that this reflex can be attenuated by prior administration of morphine. However, some patients may receive morphine, e.g., for analgesia after they have suffered severe hemorrhage. The aim of this study was to determine whether an established bradycardia and hypotension could be reversed by morphine. METHODS: Four groups of male Wistar rats (236-258 g) were anesthetized with alphadolone/alphaxalone (16-19 mg x hg x h(-1) intravenously). All groups received a hemorrhage of 40% total blood volume (BV) at 2% BV x min(-1). After the loss of 27% BV, bradycardia and hypotension were established equally in groups I and II and III and IV. Groups I (n=8) and III (n=10) received 0.9% saline (20 microL intracerebroventricularly or 1 mL x kg(-1) intravenously, respectively), whereas groups II (n=10) and IV (n=10) received morphine (10 microg intracerebroventricularly or 0.5 mg x kg(-1) intravenously, respectively). RESULTS: In groups I and III, heart rate and mean arterial blood pressure continued to fall, whereas the bradycardia was completely reversed and the hypotension partly reversed in groups II and IV after treatment with morphine. CONCLUSION: Morphine, administered centrally or peripherally, can reverse the bradycardia and markedly can attenuate the hypotension associated with severe hemorrhage. However, any benefit may be more apparent than real because other studies suggest that mortality may be increased.

Transient suppression of pancreatic endocrine function in patients following brain death.

To investigate pancreatic endocrine function in brain-dead patients, an intravenous glucose tolerance test (i.v. GTT) was performed in 8 brain-dead subjects maintained using the combined administration of vasopressin (ADH) and catecholamines during the first 3 days following the onset of brain death. Ten healthy adults served as control subjects. Although plasma glucose concentrations markedly increased and exceeded 300 mg/dl in most subjects just after the onset of brain death, they decreased to less than 200 mg/dl in most subjects after 24 h. The early insulin release also was significantly lower in brain dead subjects compared to controls (p < 0.01). The late insulin release was not decreased compared to controls but rather increased, which was accompanied by decreased glucose disappearance rate. The early insulin release recovered rapidly during the first 3 days following brain death without significant changes in the plasma hormone concentrations such as epinephrine, human growth hormone, thyroid-stimulating hormone, triiodothyronine, thyroxine, cortisol, and glucagon. The early insulin release and the plasma glucose concentration just before i.v. GTT was negatively correlated (R = -0.55, p < 0.05). We suggest awaiting recovery from hyperglycemia and early insulin release provides a reasonable approach to transplantation of the pancreas.