The effects of hyperoxia on oxygen uptake during acute anemia

The effects of normobaric hyperoxia on the oxygen uptake (VO2) and cardiovascular responses of the whole body and hindlimb during anemia were investigated. Anesthetized, paralyzed dogs were ventilated for 20-min periods with room air (normoxia), 100% O2 (hyperoxia), and returned to room air. Anemia (hematocrit = 15%) was then induced by isovolemic dextran-for-blood exchange and the normoxia, hyperoxia, normoxia sequence was repeated. Whole body VO2 and cardiac output rose following anemia, and then fell (p less than 0.05) with hyperoxia during anemia. These responses were not abolished by beta-blockade with propranolol (1 mg/kg, iv) or bilateral vagotomy. The hindlimb data for blood flow and VO2 were similar in direction to those of the whole body but were more variable. Section of the sciatic and femoral nerves did not appear to have significant effect on the limb responses to hyperoxia. The decrease in whole body and hindlimb VO2 with hyperoxia during anemia may have resulted from a redistribution of capillary blood flow away from exchange vessels in response to the elevated PO2.     

The role of D-dimers in the diagnosis of acute aortic dissection

Acute aortic dissection (AAD) is a life threatening cardiovascular medical emergency with a poor prognosis. To explore the utility of D-dimers (DD) in the diagnosis of AAD, we performed a prospective study and conducted a meta-analysis of previous studies. 368 suspected patients were enrolled, including AAD n = 89, PE n = 12, AMI n = 167, normal controls n = 100. All patients had a DD test immediately after admission. We then performed a comprehensive computer search to identify studies investigating using DD as a screening tool for AAD. Finally, we pooled these data to estimate sensitivity, specificity, positive and negative likelihood ratios (LRs) by using DerSimonian–Laird random-effects models. The DD concentrations in the AAD group were significantly higher than those in the AMI and normal control groups. However, the DD level of 500 ng/ml had a poor sensitivity of 51.7 % and specificity of 89.2 % in the diagnosis of AAD. Subgroup analyses found that DD only showed a well discriminative ability of distinguishing AAD patients from normal controls (specificity and positive LR was 97 % and 17.2, respectively). The pooled sensitivity, specificity, positive and negative LR in our meta-analysis was 89, 68 %, 2.71, 0.07, respectively. In conclusion, our results suggest that plasma DD levels cannot add to the certainty of AAD diagnosis and it is not a good biomarker for AAD. In the future, prospective research on patients from many parts of the world is warranted to validate our findings. In addition, different controls, methods of plasma DD assays and other factors should be considered.     

The essential role of carotid body chemoreceptors in sleep apnea

Sleep apnea is attributable, in part, to an unstable ventilatory control system and specifically to a narrowed "CO2 reserve" (i.e., the difference in P(a)CO2 between eupnea and the apneic threshold). Findings from sleeping animal preparations with denervated carotid chemoreceptors or vascularly isolated, perfused carotid chemoreceptors demonstrate the critical importance of peripheral chemoreceptors to the ventilatory responses to dynamic changes in P(a)CO2. Specifically, (i) carotid body denervation prevented the apnea and periodic breathing that normally follow transient ventilatory overshoots; (ii) the CO2 reserve for peripheral chemoreceptors was about one half that for brain chemoreceptors; and (iii) hypocapnia isolated to the carotid chemoreceptors caused hypoventilation that persisted over time despite a concomitant, progressive brain respiratory acidosis. Observations in both humans and animals are cited to demonstrate the marked plasticity of the CO2 reserve and, therefore, the propensity for apneas and periodic breathing, in response to changing background ventilatory stimuli.     

Hindlimb vascular responses to sympathetic augmentation during acute anemia

The effect of increased sympathetic activity on skeletal muscle blood flow during acute anemic hypoxia was studied in 16 anesthetized dogs. Sympathetic activity was altered by clamping the carotid arteries bilaterally below the carotid sinus. One group (n = 8) was beta blocked by administration of propranolol (1 mg/kg); a second group (n = 8) was untreated. Venous outflow from the left hindlimb was isolated for measurement of blood flow and O2 uptake (VO2). After a 20-min control period, both carotid arteries were clamped (CC) for 20 min followed by a 20-min recovery period. The sequence was repeated after hematocrit was lowered to about 15% by dextran exchange for blood. Prior to anemia, CC did not alter cardiac output or limb blood flow in either group. After induction of anemia, hindlimb resistance was higher with CC in the beta block than in the no block group. Both limb blood flow and VO2 fell in the beta-block group with CC during anemia. Beta block also prevented the additive increases in whole body VO2 seen with CC and induction of anemia. The data showed that the increased vasoconstrictor tone that was obtained with beta block during anemia was successful in redistributing the lower viscosity blood away from resting skeletal muscle, even to the point that muscle VO2 was decreased.     

Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the new-born lamb

We tested to see whether the steady-state hypoxic sensitivity of aortic chemoreceptors was re-set during the first 2-3 weeks of post-natal life. Aortic chemo-receptor activity was recorded from the distal end of the cut aortic branch of the cervical vagus in pentobarbitone - anesthetized, new-born lambs. Two groups were studied, the first aged 1-4 days and the second aged 10-19 days. Chemoreceptor discharge increased as hyperbolic function with increasing isocapnic hypoxia in both groups and we quantified the position and the shape of this response curve. It was shifted to the right significantly in the older group of lambs, the mean vertical asymtote increasing from 10.00 to 27.95 torr PO2. No significant difference was found in the horizontal asymotote or in the 'shaping term' between the two groups. The greatest differences between the stimulus-response curves of the two groups of animals with respect to the mean level of discharge and the slope of the curve occurred when PaO2 was below ca. 50 torr. The aortic chemoreceptors of older lambs were unable to maintain a sustained discharge at arterial PO2 values below ca. 30 torr. In contrast, in the younger group PO2 often had to be reduced below this level before discharge increased significantly. We conclude that, like the carotid chemoreceptors, aortic chemoreceptor sensitivity is re-set over the first few weeks of life. The re-setting may contribute to the increase in the ventilatory response to hypoxia which occurs over this period.     

The role of oxidative stress in hemolytic anemia

The oxidative status of cells is determined by the balance between pro-oxidants and antioxidants. Pro-oxidants, referred to as reactive oxygen species (ROS), are classified into radicals and nonradicals. The radicals are highly reactive due to their tendency to accept or donate an electron and attain stability. When cells experience oxidative stress, ROS, which are generated in excess, may oxidize proteins, lipids and DNA - leading to cell death and organ damage. Oxidative stress is believed to aggravate the symptoms of many diseases, including hemolytic anemias. Oxidative stress was found in the beta-hemoglobinopathies (sickle cell anemia and thalassemia), glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, congenital dyserythropoietic anaemias and Paroxysmal Nocturnal Hemoglobinuria. Although oxidative stress is not the primary etiology of these diseases, oxidative damage to their erythroid cells plays a crucial role in hemolysis due to ineffective erythropoiesis in the bone marrow and short survival of red blood cells (RBC) in the circulation. Moreover, platelets and polymorphonuclear (PMN) white cells are also exposed to oxidative stress. As a result some patients develop thromboembolic phenomena and recurrent bacterial infections in addition to the chronic anemia. In this review we describe the role of oxidative stress and the potential therapeutic potential of anti-oxidants in various hemolytic anemias.     

Hindlimb skeletal muscle blood flow during sympathetic nerve block before and during acute anemia

The role of sympathetic innervation in the regulation of hindlimb skeletal muscle blood flow (QL) and metabolism was studied prior to and during acute anemia in anesthetized, paralyzed, and ventilated dogs (n = 8). Neural activity in the sciatic nerve was reversibly cold blocked for a 15-min period at control hematocrit (Hct., 51%) and again at 30 min of anemia (Hct., 14%). At the end of each experiment the sciatic nerve was transected and maximally stimulated (frequency, 10 Hz; duration, 2.0 ms). Arterial blood pressure and QL were measured continuously; skeletal muscle vascular hindrance (ZL) and oxygen uptake (VO2) were calculated. When the sciatic nerve was cold blocked prior to and during anemia, ZL decreased to the same absolute value and VO2 remained unchanged. Prior to anemia the mean QL increased (p less than 0.05) from 99 to a peak value of 165 mL.kg-1.min-1 during cold block; QL had returned to control by 10 min of cooling. During anemia, QL increased (p less than 0.05) from 160 to 307 mL.kg-1.min-1 during sympathetic cold block, while maximal sympathetic stimulation decreased QL to 87 mL.kg-1.min-1. QL remained above (p less than 0.05) the anemia control value (160 mL.kg-1.min-1) at 10 min of cooling. Hindrance increased from 0.30 to 0.38 peripheral resistance units/centipoise following the induction of anemia and this was shown to be sympathetically mediated because hindrance was decreased to the same level during cold block prior to and during anemia.     

Effects of erythrocyte flexibility on microvascular perfusion and oxygenation during acute anemia

Responses to exchange transfusion using red blood cells (RBCs) with normal and reduced flexibility were studied in the hamster window chamber model during acute moderate isovolemic hemodilution to determine the role of RBC membrane stiffness in microvascular perfusion and tissue oxygenation. Erythrocyte stiffness was increased by 30-min incubation in 0.02% glutaraldehyde solution, and unreacted glutaraldehyde was completely removed. Filtration pressure through 5-microm pore size filters was used to quantify stiffness of the RBCs. Anemic conditions were induced by two isovolemic hemodilution steps using 6% 70-kDa dextran to a hematocrit (Hct) of 18% (moderate hemodilution). The protocol continued with an exchange transfusion to reduce native RBCs to 75% of baseline (11% Hct) with either fresh RBCs (RBC group) or reduced-flexibility RBCs (GRBC group) suspended in 5% albumin at 18% Hct; a plasma expander (6% 70-kDa dextran; Dex70 group) was used as control. Systemic parameters, microvascular perfusion, capillary perfusion [functional capillary density (FCD)], and oxygen levels across the microvascular network were measured by noninvasive methods. RBC deformability for GRBCs was significantly decreased compared with RBCs and moderate hemodilution conditions. The GRBC group had a greater mean arterial blood pressure (MAP) than the RBC and Dex70 groups. FCD was substantially higher for RBC (0.81 +/- 0.07 of baseline) vs. GRBC (0.32 +/- 0.10 of baseline) and Dex70 (0.38 +/- 0.10 of baseline) groups. Microvascular tissue Po(2) was significantly lower for Dex70 and GRBC vs. RBC groups and the moderate hemodilution condition. Results were attributed to decreased oxygen uploading in the lungs and obstruction of tissue capillaries by rigidified RBCs, indicating that the effects impairing RBC flexibility are magnified at the microvascular level, where perfusion and oxygenation may define transfusion outcome.     

The role of glycolysis in the protective effect of amtizol during acute hypoxia

In rats, protective effect of amtizol was found to depend on the rate of carbohydrate substrate in the organism as well as on the glycolysis activity. Amtizol was able to activate utilising of carbohydrates in a glycolytic way in satisfied rats with a blockade of glycolysis by monoiodacetate, whereas glyconeogenesis was activated in starving rats.