Cardiorespiratory adjustments in chronic sickle cell anemia

During the intercrisis periods, patients homozygous for sickle cell anemia (SS) show clinical symptoms of severe impairment of oxygen transport mechanisms. We have determined respiratory lung function tests, arterial and venous blood gases and cardiocirculatory parameters in 39 SS patients (mean age 22 +/- 5 yr) at distance from any vaso-occlusive crisis or blood transfusion. The patient group was compared to subjects homozygous for HbA (AA) of the same ethnic origin. Determinations were made at rest and after a 5 min mild exercise period. The main alterations in oxygen transport parameters observed in SS patients were: 1) a moderate reduction in vital capacity and maximal ventilation (pure restrictive syndrome), 2) an arterial hypoxemia which worsened the already low oxygen content of blood due to anemia, and 3) a low arterio-venous oxygen saturation difference which is very surprising in anemic patients. The normal oxygen consumption rate was thus insured by a 70% increase of the cardiac output at rest. A particular abnormality found in SS patients was the high Po2 in mixed venous blood. The decreased affinity of blood for oxygen resulting from the polymerization of HbS in the erythrocytes led to an almost normal venous blood unsaturation and thus a decreased release of oxygen from this anemic blood. These results indicate that peripheral blood flow was permanently increased in SS patients. This may be in part at the origin of the arterial hypoxemia induced by an increased pulmonary blood shunting. Sickle cell anemia is more severe than other anemias of comparable intensity as, due to the sickling process, these patients appear to be at the upper limit of physiological compensatory mechanisms usually encountered in chronic anemia.     

Effect of an allosteric modifier of hemoglobin, RSR-4, on oxygen affinity and oxygen saturation of hemoglobin in rabbits

Theoretically, if the arterial partial oxygen pressure (PaO2) does not change, a right shift in the oxygen equilibrium curve (OEC) of hemoglobin should reduce arterial oxygen saturation. In this study we investigate whether a right shift in the OEC of hemoglobin decreases transcutaneous oxygen saturation (Tc-SO2) following the administration of an allosteric effector, 2-[4-(((3, 5-dichloroanilino)-carbonyl) methyl) phenoxy]-2-methylpropionic acid (RSR-4). The effect of RSR-4 on hemoglobin oxygen affinity was studied in four New Zealand white male rabbits. Following intraperitoneal administration of RSR-4, Tc-SO2 decreased in a dose-dependent manner. P50 (partial oxygen pressure at 50% hemoglobin oxygen saturation) in whole blood increased as the concentration of RSR-4 increased. Tc-SO2 decreased as whole-blood affinity (1/P50) decreased. There was no positive correlation between Tc-SO2 and PaO2. We concluded that a decrease in hemoglobin oxygen affinity following RSR-4 administration reduced arterial oxygen saturation. This decrease in the presence of an allosteric effector such as RSR-4 in vivo can be detected and monitored as a reduction in Tc-SO2.     

Effects of altering O2 delivery on VO2 of isolated, working muscle.

Maximal oxygen consumption (VO2 max) and muscle blood flow (Q max) were measured in an isolated gracilis muscle preparation before and after alteration in perfusion pressure (BP), arterial oxygen saturation (SaO2), and hemoglobin concentration (Hb). Q varied directly with BP and inversely with Hb (viscosity) but was unaffected by changes in arterial SaO2. VO2 max varied directly with oxygen delivery under all conditions. These results indicate that VO2 max is normally limited by oxygen delivery rather than any intrinsic limiting of oxygen consumption of the muscle.     

Oxygen-linked CO2 transport in sheep blood.

We have analyzed oxygen-linked carbamate formation in sheep hemoglobin B by measuring a) the effect of CO2 on oxygen affinity and Bohr effect in red cell suspensions and dilute (1.3 mM Hb4) and concentrated (5 mM Hb4) hemoglobin solutions at 37 degrees C and b) CO2 binding curves of deoxygenated and oxygenated whole blood and hemoglobin solutions, respectively, at the same temperature. In the presence of CO2 both the Bohr effect and oxygen affinity were significantly lower in 1.3-mM Hb4 solutions than in either red cell suspensions or 5-mM Hb4 solutions, while in the absence of CO2 Bohr effect and oxygen affinity did not differ significantly in those preparations. Likewise, the fraction of oxygen-linked carbamate obtained from CO2 binding curves was found to be higher in 1.3-mM Hb4 (0.156 M HbCO2/M HbO2) solutions than in 5-mM Hb4 solutions (0.12 M HbCO2/M HbO2) at pH 7.2. We conclude that hemoglobin concentration affects formation of oxygen-linked carbamate. Total oxygen-linked CO2 in sheep whole blood amounted to 0.18 M CO2/M O2 of which 70% is oxygen-linked carbamate. Assuming a respiratory quotient of 0.85, the contribution of oxygen-linked CO2 to carbon dioxide exchange in sheep blood was computed to be 21%.     

Sudden infant death syndrome: respiratory causes

Sudden infant death syndrome (SIDS) claims one in five hundred babies between 1 and 12 months of life. Since no cause of death is found at autopsy, SIDS has been and often remains a complete enigma for pediatricians, physiologists and forensic pathologists. However, there is growing evidence from careful epidemiologic, pathologic and physiologic studies that subtle changes occur in those babies for a variable period of time before death. Some of these data are reviewed and interpreted in the light of the sleep apnea-hypoventilation inducing chronic hypoxemia hypothesis. It appears that no single factor is characteristic of, or responsible for, SIDS; rather, a combination of different adverse circumstances occurring during a period of increased vulnerability may cause the fatal outcome in some infants. Some preventive aspects of SIDS in low birth weight babies, siblings of SIDS victims and near-miss SIDS are discussed.     

Association of sudden infant death syndrome with grossly deranged iron metabolism and nitric oxide overload

Sudden infant death syndrome (SIDS) occurs silently usually during sleep and, though remaining unexplained after autopsy, leaves footprints creating a pattern analogous to that which follows a flood of nitric acid (NO). These footprints in SIDS are associated with serious pathological changes, viz. elevated hepatic iron, bone marrow hyperplasia, hypomyelinated respiratory control centres, elevated lung immunoglobulins, cerebral hypoperfusion resembling lesions induced by chronic hypoxemia, ischemia, congenital heart disease and congenital myopathy. Hypoxia stimulates the immune response and the over-arousal of the immune response triggers a flood of NO. Adenosine triggers sleep. NO and adenosine are additive as dilators of coronary blood vessels. Blood pressure collapses. Selenium increases the activity of the enzyme ferrochelatase during incorporation of heme into cytochrome oxidase. NO binds to cytochrome oxidase, inhibiting respiration. When NO reaches dangerous levels, the cell turns on production of heme oxygenase. Heme is broken down to iron (Fe) carbon monoxide (CO) and bile pigments. NO has a huge affinity for hemoglobin which catalyses NO degradation to nitrate. Furthermore, NO is a product of smoke and SIDS incidence is higher in smoking mothers.     

Anaphylaxis in the monkey: hemodynamics and blood flow distribution.

Aggregate anaphylaxis was induced in eight ovalbumin-sensitized monkeys (Macaca irus). Hemodynamics, blood flow distribution and myocardial performance were studied. Following challenge, severe circulatory shock developed. Systemic arterial and left atrial pressures decreased and pulmonary arterial and right atrial pressures increased. There was a tenfold increase in pulmonary vascular resistance, and cardiac output was markedly reduced (-75%). A redistribution of the blood flow to vital organs (brain, heart and liver) occurred, at the expense of flow to other regions (muscles, kidneys, pancreas and spleen). There was also a redistribution of the blood flow within the myocardium, resulting in an unchanged right ventricular blood flow, despite a decrease in total myocardial blood flow. Right ventricular stroke work was reduced in spite of high filling pressures, whereas the decrease in left ventricular stroke work coincided with low filling pressures. It is concluded that the initial main cause of the low outflow state was an increased resistance in the pulmonary circulation followed by acute right heart failure.     

Anaphylaxis in the monkey: hemodynamics and blood flow distribution

Aggregate anaphylaxis was induced in eight ovalbumin-sensitized monkeys (Macaca irus). Hemodynamics, blood flow distribution and myocardial performance were studied. Following challenge, severe circulatory shock developed. Systemic arterial and left atrial pressures decreased and pulmonary arterial and right atrial pressures increased. There was a tenfold increase in pulmonary vascular resistance, and cardiac output was markedly reduced (-75%). A redistribution of the blood flow to vital organs (brain, heart and liver) occurred, at the expense of flow to other regions (muscles, kidneys, pancreas and spleen). There was also a redistribution of the blood flow within the myocardium, resulting in an unchanged right ventricular blood flow, despite a decrease in total myocardial blood flow. Right ventricular stroke work was reduced in spite of high filling pressures, whereas the decrease in left ventricular stroke work coincided with low filling pressures. It is concluded that the initial main cause of the low outflow state was an increased resistance in the pulmonary circulation followed by acute right heart failure.     

Hemoglobin Beth Israel. A mutant causing clinically apparent cyanosis.

We found that an abnormal hemoglobin with a very low oxygen affinity was responsible for overt cyanosis in an otherwise healthy adolescent. Hemoglobin Beth Israel, in which serine replaces the asparagine residue normally present at position 102 (G4) of the beta-polypeptide chain, was associated with normal blood counts and no apparent exercise intolerance in the heterozygous carrier. Cyanosis resulted from a drastically right-shifted oxygen dissociation curve, whose position and shape could account for the absence of "physiologic" anemia. The whole-blood oxygen tension at 50 per cent oxygen saturation was 88 mm Hg (normally 26 +/- 1 mm Hg), and the arterial blood was only 63 per cent saturated with oxygen despite a normal oxygen tension of 97 mm Hg. The hemolysate showed a low oxygen affinity but normal Bohr effect. Unexplained cyanosis, particularly in association with normal arterial oxygen tension should prompt a search for an abnormal hemoglobin, which may obviate the need for invasive diagnostic procedures.     

Peripheral arterial chemoreceptors and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is the major cause of death in infants between 1 month and 1 year of age. Two particular concerns are that (1) premature or low birth weight (<2500-g) infants have a 2- to 40-fold greater risk of dying of SIDS (depending on the sleep position) than infants born at term and of normal birth weight, and that (2) the proportion of premature infants dying of SIDS has increased from 12 to 34% between 1988 and 2003. Hypo- and hypersensitivity of peripheral arterial chemoreceptors (PACs) may be one biological mechanism that could help to explain the epidemiological association between the increased incidence of SIDS in formerly premature infants. Because premature infants are often exposed to the extremes of oxygen stress during early postnatal development, they are more likely to have a maladaptive response of PACs later in their lives. As the first line of defense that mediates an increase in ventilation to a hypoxic challenge during wakefulness and sleep, PACs also mediate arousal responses during sleep in response to an asphyxial event that is often associated with upper airway obstruction. In most mammalian species, PACs are not fully developed at birth and thus are vulnerable to plasticity-induced changes mediated by environmental exposures such as the extremes of oxygen tension. Hypoxic or hyperoxic exposure during early postnatal development can lead to hyposensitive or hypersensitive PAC responses later in life. Although baseline chemoreceptor activity may not be the cause of an initial hypoxic or asphyxial event, the level of peripheral chemoreceptor drive does modulate the (1) time to arousal, (2) resumption of airflow during airway obstruction, (3) escape behaviors during rebreathing, and (4) cardiorespiratory responses that result from activation of the laryngeal chemoreflex. The laryngeal chemoreflex can be stimulated by reflux of gastric contents above the upper esophageal sphincter, or an increase in nasopharyngeal secretions from upper respiratory tract infections--events that contribute to some cases of SIDS. In this review, evidence is presented that both hypo- and hypersensitivity of PACs may be disadvantageous to the premature infant who is placed in an at risk environment for the occurrence of hypoxemia/asphyxia event thereby predisposing the infant to SIDS.     

Sudden infant death syndrome Part 2: the response of the reticuloendothelial system to hypoxemia and infection.

The incidence of ascites in chicks raised in a high-altitude chamber doubled from 6500 feet to 8000 feet. A similar condition developed in calves transported to pasture at high altitude. Chicks raised in a high-altitude chamber (compared to controls) produced more plasma cells in the germinal centres of the spleen about four days after an antigen challenge. Children usually suffering from a mild respiratory infection at sea level often developed pulmonary edema (HAPE) on transfer to high altitude. Sudden infant death syndrome (SIDS) victims produced more plasma cells in the germinal centers of the spleen. In one survey of SIDS, about half of the infants suffered an upper respiratory tract infection in the two weeks prior to death and the lungs were filled with fluid at autopsy. Elevated levels of hypoxanthine indicated hypoxemia before death, and a presumed response to hypoxemia in SIDS was the presence of extramedullary hematopoiesis in the liver.The effect of prolonged hypoxemia and infection are additive in increasing vascular permeability and the accumulation of edema fluid. The preferential uptake of zinc by edema fluid proteins at the expense of inflammatory cells increases the motility and metabolism of zinc-deprived activated macrophages. Activated macrophages release cytokines which in turn stimulate the release of pro-inflammatory peptides which increase vascular permeability and mortality. These inflammatory peptides are under proteolytic control. The neutral endopeptidase (NEP) is a cell-surface zinc metalloproteinase which modulates toxic shock.Zinc also modulates the inflammatory response of the activated macrophage. Interleukin-12 (IL-12), predominantly a product of macrophages, is involved in regulating both hematopoiesis and the adaptive immune response. IL-12 promotes interferon gamma (IFNgamma) production by T cells. IFNgamma acts on macrophages to release large amounts of nitric oxide (NO). An elevated immune response leads to NO overload, dilation of the cardiovascular system and toxic shock. A mechanism resulting in cardiovascular failure and a shock-like sequence is described in some cases of SIDS.Bradycardia, recorded on cardiorespiratory monitors in six SIDS infants, was considered a late event. Cytokines regulate all aspects of the immune response.Extramedullary hematopoiesis in the liver was one anatomical marker of hypoxemia in SIDS. This survey traces the function of the activated macrophage with the cytokines regulating extramedullary hematopoiesis and the precocious immune response in SIDS.     

Seasonal changes in blood oxygen transport and acid-base status in the tegu lizard, Tupinambis merianae

Oxygen-binding properties, blood gases, and acid-base parameters were studied in tegu lizards, Tupinambis merianae, at different seasons and temperatures. Independent of temperature and pH, blood oxygen affinity was higher in dormant lizards than in those active during the summer. Haematocrit (Hct) and hemoglobin content ([Hb]) were greater in active lizards resulting in a higher oxygen-carrying capacity. Nucleoside triphosphate content ([NTP]) was reduced during dormancy, but the ratio between [NTP] and [Hb] remained unchanged. Dormancy was accompanied by an increase in plasma bicarbonate ([HCO-(3)]pl) and an elevation of arterial CO2 partial pressure (PaCO2) and CO2 content in the plasma (CplCO2). These changes in acid-base parameters persist over a broad range of body temperatures. In vivo, arterial O2 partial pressure (PaO2) and O2 content (CaO2) were not affected by season and tended to increase with temperature. Arterial pH (pHa) of dormant animals is reduced compared to active lizards at body temperatures below 15 degrees C, while no significant difference was noticed at higher temperatures.     

Pulmonary arteriovenous malformations. Physiologic observations and results of therapeutic balloon embolization

Pulmonary arteriovenous malformations can result in severe hypoxemia and dyspnea. We measured pulmonary function, arterial blood gases, and hemodynamics in 10 patients with such malformations. Pulmonary-function tests were normal, but hypoxemia was associated with chronic hyperventilation at rest (mean, 12 liters per minute; mean carbon dioxide tension, 28 mm Hg). With exercise, ventilation increased more than expected for the level of carbon dioxide production. Balloon embolization of 58 of the 71 visible vascular malformations in the 10 patients resulted in an increase in arterial oxygen tension (43 vs. 64 mm Hg; P less than 0.001) and hemoglobin saturation (79 vs. 92 per cent; P less than 0.001). Nine patients had improved exercise tolerance. Forty-eight to 72 hours after correction of the hypoxemia, resting ventilation had decreased but was still above normal (mean, 9.3 liters per minutes; mean carbon dioxide tension, 29 mm Hg). We conclude that ventilatory responses in these patients are similar to those of people from sea-level areas who are acclimated to high altitudes and that dyspnea is due to inappropriately high levels of ventilation for a given workload under hypoxic conditions.     

Elevated fetal hemoglobin levels in sudden infant death syndrome

The cause of sudden infant death syndrome (SIDS) is unknown, although deficits in cardiopulmonary function and central respiratory control have been suggested as possible mechanisms of the disorder. In this study, we tested the hypothesis that SIDS is associated with a delay in the maturation of hematopoiesis. Prolonged elevation in the levels of fetal hemoglobin (hemoglobin F) in infants with SIDS could denote a compromised delivery of oxygen to sensitive tissue sites. Normally, hemoglobin F (alpha 2 gamma 2) is largely replaced by adult hemoglobin, hemoglobin A (alpha 2 beta 2), during the first six months after birth. Using an isoelectric-focusing procedure for measuring stable hemoglobin subunits, we quantitated the levels of hemoglobin F in blood samples from 59 patients with SIDS and 40 controls (32 living and 8 dead) matched for postconceptional age. The level of hemoglobin F in the population with SIDS was significantly higher than that in the controls in the age range tested (39 to 75 weeks); the mean (+/- SEM) proportion of hemoglobin F was 63.2 +/- 3.6 percent in the group with SIDS, as compared with 48.1 +/- 5.0 percent in the controls (P less than 0.025). The difference in hemoglobin F levels was most pronounced 50 weeks after conception: the proportion of hemoglobin F in the 37 patients with SIDS with a postconceptional age of more than 50 weeks was 47.4 +/- 3.6 percent, as compared with 18.8 +/- 3.1 percent in the 19 controls of that age (P less than 0.0005). We conclude that hemoglobin F is a useful postmortem marker for the population with SIDS that we studied and that it may have value as a prospective marker for some infants at risk for SIDS.     

Physiologic responses of cross-linked hemoglobin in endotoxin-treated rats

Purified human cross-linked hemoglobin (alpha alpha Hb) as well as recombinant human hemoglobin is undergoing clinical trials in the setting of acute blood loss and perioperative hemodilution. We have previously demonstrated that in rabbits with circulating plasma Hb, such as alpha alpha Hb, infusion of endotoxin (LPS) impairs myocardial contractility which results in hypotension, tissue hypoperfusion and increased mortality. The untoward cardiovascular effects occurring after the combined infusion of LPS and alpha alpha Hb in this model are similar to those reported for other agents that inhibit nitric oxide (NO) availability. To determine if the deleterious effects of alpha alpha Hb and LPS were species specific, we performed similar studies in rats. Anesthetized Sprague-Dawley rats received LPS (4 mg/kg or 40 mg/kg) alone or in combination with alpha alpha Hb (0.7 g/kg). Mean arterial blood pressures (MAP) increased in the group that received alpha alpha Hb alone (105 +/- 8 to 120 +/- 7 mm Hg, p = 0.2) and a decrease was noted in the groups that received low dose LPS (4 mg/kg, p = 0.5) and high dose LPS (40 mg/kg, p = 0.016). MAP in rats treated with the LPS at either dose combined with alpha alpha Hb remained unchanged. Levels of urine nitrite, which was measured as a surrogate marker for plasma NO, were significantly decreased at 2 hr in groups that received the combination of alpha alpha Hb and LPS at 4 mg/kg (p = 0.022) and 40 mg/kg (p = 0.003). No significant decrease was observed in animals treated only with alpha alpha Hb (p = 0.21) or LPS (4 mg/kg; p = 0.78 and 40 mg/kg; p = 0.65). Survival was evaluated during 72 hr in animals that were infused with high dose LPS (40 mg/kg) alone or in combination with alpha alpha Hb and then allowed to recover. The survival of rats treated with LPS alone or the combination was 29% at the end of 24 hr and was 100% for rats receiving only alpha alpha Hb. The data suggest that the toxicity of alpha alpha Hb appears to be a species specific phenomenon.     

Physiologic effects of normal-or low-oxygen-affinity red cells in hypoxic baboons.

Baboons were bled one-third their red cell mass and were given homologous transfusions of red blood cells to restore the red cell volume. One group of baboons received red blood cells with a normal 2,3-diphosphoglycerate 2,3-DPG) level and normal affinity for oxygen, and in this group the 2,3-DPG level after transfusion was normal. The other group received red blood cells with a 160% of normal 2,3-DPG level and decreased affinity for oxygen, and in this group the 2,3-DPG level after transfusion was 125% of normal. In both groups of baboons, the inspired oxygen concentration was lowered and arterial PO2 tension was maintained at 55-60 mmHg for 2 h after transfusion. During the hypoxic state, systemic oxygen extraction was similar in the two groups, whereas oxygen saturation was lower in the high 2,3-DPG group than in the control animals. Cardiac output was significantly reduced 30 min after the arterial PO2 was restored to normal. These data indicate that red blood cells with decreased affinity for oxygen maintained satisfactory oxygen delivery to tissue during hypoxia.     

Oxygen delivery in lambs: cardiovascular and hematologic development

After birth a decrease in hemoglobin concentration occurs while high metabolic demands are imposed on the infant by the extrauterine environment. Using the resting lamb as a model, we studied the mechanisms that are called into play during this period to maintain oxygen delivery. Measurements were made of oxygen consumption, arterial and mixed venous blood oxygen contents, cardiac output, hemoglobin concentration, percent fetal hemoglobin, 2,3-diphosphoglycerate, and hemoglobin oxygen affinity during the first two postnatal months. There was a rapid decrease in hemoglobin concentration after birth and concomitant decrease in hemoglobin oxygen affinity, changes similar to those described in humans. Cardiac output and oxygen consumption were both very high immediately after birth and declined in parallel, so that arteriovenous oxygen content difference was constant. Thus at rest cardiac output varies as a result of the changing need for oxygen. This relationship is independent of hemoglobin concentration or oxygen affinity within the normal range. If, however, oxygen demands were increased, oxygen delivery might be compromised by a limited ability to increase oxygen extraction during the immediate newborn period or when hemoglobin concentration is lowest.     

Hemoglobin oxygen affinity in patients suffering from arterial occlusive disease of the legs

Summary Parameters characterizing the hemoglobin oxygen affinity were determined in blood of 12 male patients suffering from arterial occlusive disease (AOD) of the legs and compared with data obtained earlier from healthy human subjects (controls). Due to a COHb content of 4.8%±2.2% in the cigarette-smoking AOD patients, the standard oxygen dissociation curve (ODC) was left-shifted, the half-saturation pressure (P₅₀) amounted to 24.8±1.7 mmHg (3.30±0.23 kPa), although the 2,3-diphosphoglycerate concentration was increased to 15.3±1.7 µmol/g Hb. Correcting the effects of elevated COHb shifts the P₅₀ to 26.3 mmHg (3.5 kPa) and increases the steepness of the ODC (Hill's n) from 2.79±0.27 to about 2.99, which is significantly different from controls. The Bohr coefficients after acidification of blood with lactic acid (BC_Lac) show high values at low oxygen saturations of hemoglobin (–0.50±0.04 in AOD patients, –0.32±0.04 in controls;P<0.05 at 10% S_O2). The cause of the alterations in hemoglobin oxygen affinity may be a reduced mean erythrocyte age, but also the influence of unknown factors generated, e.g., from anaerobic muscle metabolism in AOD.Abbreviations AOD Arterial occlusive disease of the legs - BC Bohr coefficient - BC_CO2 Bohr coefficient after acidification of blood with CO₂ - BC_Lac Bohr coefficient after acidification of blood with lactic acid - DPG 2,3-Diphosphoglycerate - ODC Oxygen dissociation curve - P₅₀ Oxygen pressure when hemoglobin is half-saturated     

Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia

Two polycythemic subjects from a family with multiple polycythemic subjects were evaluated. Estimation of oxygen affinity of Hb from venous blood gas parameters (P50) revealed low P50 suggesting a high affinity Hb variant. Further work up, which included beta globin gene sequencing, revealed a novel mutation changing a codon to the previously reported high affinity Hb - Hb Johnstown (beta 109 Val->Leu). Polycythemic subjects with high affinity Hb variant are asymptomatic with normal life expectancy. Their differentiation from polycythemia vera (PV) is crucial to avoid therapy which is otherwise reserved for PV patients. We provide an electronic version (in Microsoft excel program) of a previously reported mathematical formula for rapid calculation of P50 from venous blood gases. Estimation of P50 is an essential initial step in the evaluation of a subject with personal and family history of polycythemia.