Effects of recombinant human erythropoietin and interleukin-3 on erythropoietic recovery from acute anemia.

The risks inherent in the use of homologous blood products have increased efforts toward identifying alternatives to transfusion. We have previously shown that the administration of recombinant human erythropoietin (rhEpo) enhances the erythropoietic response to acute blood loss. Recombinant human interleukin-3 (rh-IL-3) is a hematopoietic growth factor that has been shown to act synergistically with rhEpo in accelerating erythropoiesis in vitro. The purpose of this study in a primate model was to determine if the administration of rhIL-3 in combination with rhEpo could augment the erythropoietic response to acute blood loss more than rhEpo therapy alone. Twenty-four adult male baboons were randomized into four groups. The induction of acute normovolemic anemia to a hematocrit of 20% was accomplished via exchange-transfusion with 6% hetastarch. The groups were then treated for 7 consecutive days with the following growth factors: group I (n = 7), no growth factors; group II (n = 5), rhIL-3 alone (100 micrograms/kg/d); group III (n = 6), rhEpo alone (1000 U/kg/d); group IV (n = 6), rhEpo (1000 U/kg/d) plus rhIL-3 (100 micrograms/kg/d). All animals received folate, vitamin B12, and intravenous iron-dextran immediately following the exchange-transfusion. Response to therapy was monitored for 35 days. There were no adverse reactions following growth factor administration. The analysis of erythropoietic rates between study days 1 through 11, as determined via linear regression analysis, revealed that hematocrits increased significantly faster in the groups receiving rhEpo compared to controls. The administration of rhIL-3, however, did not increase the rate of erythropoiesis when compared to controls, nor did it augment response when added to the rhEpo regimen. The results of this study demonstrate that the administration of rhIL-3 alone had no significant effect on erythropoiesis in this setting of acute blood loss. Further, despite promising in vitro data, rhIL-3 provided no additional stimulation of erythropoiesis in animals receiving rhEpo. Nevertheless, the study confirms that the pharmacologic acceleration of erythropoiesis by rhEpo alone remains an attractive alternative to homologous transfusion.

Pharmacokinetics and milk residues of butorphanol in dairy cows after single intravenous administration.

The pharmacokinetics of butorphanol tartrate were investigated following intravenous administration of 0.25 mg/kg of body weight to six healthy non-lactating Jersey cows. Three lactating Holstein cows also received 0.045 mg of butorphanol/kg of body weight intravenously to determine the extent and duration of drug transfer into milk. A radioimmunoassay technique was used to measure butorphanol concentrations in plasma and milk. The disposition of butorphanol following intravenous administration was characterized by rapid and extensive distribution followed by a slower elimination phase. Apparent volume of distribution was 4.178 +/- 1.145 (mean +/- SD) 1/kg, mean elimination half-life was 82 min, and clearance was 34.6 +/- 7.7 ml/min/kg. Trace quantities of butorphanol were detected in the cow's milk for up to 36 h following administration. These pharmacokinetic data were compared with pharmacokinetic and pharmacodynamic data for butorphanol in other species and for three other potent opioids in related ruminant species.

Partial uterine prolapse associated with uterine foreign body in a cow.

After correction of partial uterine prolapse in a Holstein cow, a 6-cm-long twig was found deep in the affected uterine horn. The twig was removed, and calcium-dextrose and penicillin G were administered. Recovery was unremarkable. Other reports of uterine foreign bodies in cows are scarce and do not describe uterine foreign bodies associated with uterine prolapse or invagination.

Effect of hemoglobin solution on compensation to anemia in the erythrocyte-free primate.

Hemoglobin solutions are undergoing clinical trials as erythrocyte substitutes. Some of these solutions have higher O2 affinities compared with normal erythrocyte hemoglobin. Also, they appear to interact with endothelial-derived smooth muscle relaxation. The purpose of this study was to evaluate the nature and limits of compensation to acute normovolemic anemia in the erythrocyte-free primate maintained with a hemoglobin solution. The experimental group consisted of six anesthetized paralyzed adult baboons (Papio anubis) that were exchange transfused (ET) with a pyridoxylated polymerized hemoglobin solution [hemoglobin concentration [( Hb]) = 14 g/dl, O2 half-saturation pressure of hemoglobin (P50) = 19.6 Torr] until a hematocrit less than 1% was achieved. They underwent a second ET with Dextran-70 until [Hb] = 1 g/dl. A control group (n = 6) underwent an ET with Dextran-70 until [Hb] = 1 g/dl. Both groups maintained O2 consumption (VO2) until [Hb] = 3 g/dl. Both groups were stable until [Hb] less than 1 g/dl, and both groups increased their cardiac output. The relation between VO2 and O2 delivery was similar for both groups. In vivo P50 and mixed venous O2 tension were significantly lower in the experimental group. The nature and limits of compensation to diminished O2 delivery due to anemia were similar in the two groups.

Perioperative recombinant human erythropoietin.

The risks of transfusion-associated infectious disease have made increased efforts to avoid homologous transfusion imperative. Little attention has been focused on efforts to accelerate erythropoiesis as a method of reducing homologous blood use. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study was to evaluate the effects of perioperative rHuEPO administration on postoperative erythropoiesis. Fifteen baboons were divided into three groups of five each. Group I received no rHuEPO. Group II received five daily preoperative doses of rHuEPO (1000 U/kg). Group III received five daily preoperative doses and 14 daily postoperative doses of rHuEPO (1000 U/kg). All animals underwent a laparotomy followed by an exchange transfusion to a final hematocrit of 15%. The time in days required to recover to hematocrits of 20% was significantly shorter in both groups that received preoperative doses of rHuEPO when compared with that of controls (3.3 vs 5.7 days, p less than 0.01). The recovery times to hematocrits of 25%, 30%, and baseline levels were all significantly shorter in the group that received both preoperative and postoperative doses of rHuEPO. The data show that perioperative dosage of rHuEPO significantly accelerates postoperative erythropoiesis. Perioperative administration of rHuEPO may reduce the requirements for homologous transfusion.

Subendocardial infarction in retrospect: pathologic, cardiographic, and ancillary features.

Fifty-three patients with subendocardial infarction (SEMI) were studied at autopsy; all were elderly and the group was equally divided by sex. About half had more than one SEMI; the recurrences or extensions often involved superjacent, but not infrequently adjacent, areas. Six showed fibrinous pericarditis. This larger study showed more widespread and severe coronary narrowing than an earlier report. Six patients had thrombi in the right coronary artery. Six showed electrocardiographic evidence of concomitant anteroseptal and inferior (Roesler-Dressler) infarction, and 12 had intraventricular block generally preceding higher-grade block or arrhythmias. At some time during their terminal hospitalization, 27 patients, or half, developed distinctive protracted RS-T depression or T wave inversion. Twenty-four of the SEMIs were diagnosed on accepted criteria as transmural infarct; that diagnosis was sustained in only four. Thus neither the presence of changes in RS-T segment or T wave nor the absence of QRS changes are mandatory for the diagnosis of SEMI; this invalidates the common assumption that the diagnosis is not justified unless these conditions are met.

Colloid or crystalloid in the resuscitation of hemorrhagic shock: a controlled clinical trial.

The object of this article is to assess the value of human serum albumin (HSA) in the initial resuscitation of hypotensive trauma victims. Thirty-six patients (mean age = 30 years) in shock from trauma who underwent laparotomies were randomly assigned to either Ringer's lactate solution (RL) resuscitation or 4% HSA in RL resuscitation. Both groups received approximately 8L of test fluid and 6U of washed red cells. The only death in the study occurred in a patient assigned to the RL group. Two patients in each group required mechanical ventilation for longer than 24 hours. No differences were noted in a battery of pulmonary function tests performed daily for 5 days. These results demonstrate that HSA is not essential in this clinical setting for safe and effective resuscitation.

Sick sinus syndrome with seroconstrictive pericarditis in malignant lymphoma involving the heart: a case report.

A case of the sick sinus syndrome and constrictive pericarditis with effusion (seroconstrictive pericarditis) as manifestations of lymphomatous involvement of the heart is presented. Autopsy findings documented infiltration of the sinus node by undifferentiated malignant lymphoma cells. The clinical course is described and problems with diagnosis and management of such a complication are discussed. This is one of the few cases in the literature in which an uncommon cause of conduction system disease and pericardial constriction was substantiated by electrocardiogram, angiography, and autopsy.

Compromise therapy in the patient with angina pectoris and hypothyroidism. A clinical assessment.

The teaching that thyroid replacement therapy can aggravate angina or induce myocardial infarction in patients with hypothyroidism and coronary disease, and thus compel acceptance of incomplete control of either, was substantiated in 51 patients (18 with iatrogenic and 30 with idiopathic primary hypothyroidism, and three with secondary hypothyroidism as a component of panhypopituitarism). Based upon clinical and laboratory criteria, control of hypothyroidism was unsatisfactory in two fifths of the patients. Judged by frequency and ease of induction of angina and nitroglycerine requirement, control of angina was unsatisfactory in one-third. In many patients maximal tolerated dose of thyroid varied with time. The effect of combined propranolol and thyroid therapy in 13 patients was quite satisfactory in seven patients, fair in three and poor in three, but excellent in none. Transfusions were useful as a short- or long-term expedient in a few. Of 12 patients considered for coronary revascularization, three were rejected because of other medical problems and one showed prompt improvement after the dose of thyroid was decreased. Five of the remaining eight studied by coronary cineangiography were rejected as unsuitable for surgery. The remaining three were subjected to coronary revascularization. One did well for a time, apparently until a graft became occluded, the remaining two are still doing well. Coronary bypass graft surgery may deserve a larger role in the future management of these patients.

Virus myocarditis: a critique of the literature from clinical, electrocardiographic, and pathologic standpoints.

Concurrent viral infection and myocarditis presumably indicate viral myocarditis. The electrocardiographic and pathologic changes developing during acute infection may, however, result from changes not produced by the infection itself, eg, fever, tachycardia, ischemia, potassium depletion, vitamin deficiencies, drugs. This qualification should be remembered in the evaluation of all alleged virus myocarditis. Viral infection seems to prefer the very young. Its localization in the heart is favored by general or local hypoxia, perhaps thus explaining a predilection for the subendocardium. It may be influenced by the strain of the organism or by the hormonal or immunologic state of the host. Intrauterine infection of the fetus with rubella, mumps, and perhaps coxsackievirus can induce congenital cardiac defects. The role of virus infection in precipitating acute myocardial infarction deserves further study. The value of treatment, including steroids, nonsteroidal immunosuppressive agents, and "antiviral" agents is not yet established.

Aortic valve replacement for ochronosis of the aortic valve.

A patient with generalized ochronosis developed severe cardiovascular symptoms related to ochronotic deposits on the aortic valve and in the coronary arteries. A transvalvular gradient of 100 mm Hg and obstruction of the left anterior descending coronary artery were found by catheterization. Aortic valvular replacement and aortocoronary bypass were performed successfully, and the patient has been well two years since operation. This represented the first reported case of aortic valve replacement for this rare metabolic condition. With increased mobility of these patients due to aggressive orthopedic joint treatment, more patients with this syndrome may require surgery for cardiovascular symptoms.

Crystalloid vs colloid in the etiology of pulmonary failure after trauma: a randomized trial in man.

One possible cause of pulmonary failure after trauma is the type of asanguinous fluid used for resuscitation, i.e., crystalloid or colloid. To investigate this issue, patients having a laparotomy for trauma randomly received either Ringer's lactate (RLS) alone or Ringer's lactate with albumin (ALB). Both groups received washed red cells. Test fluids and red cells were given before and during operation to restore vital signs and hematocrit to normal. Pulmonary function tests were performed for 5 days after operation. One hundred and forty-one cases were studied (84 RLS, 57 ALB). The volume of asanguinous resuscitation fluid infused was 5.37 +/- 3.38 liters (-x +/- SD) for RLS and 5.87 +/- 3.05 liters for ALB. ALB cases received 213 +/- 130 gm of albumin. Red cell transfusions were 1.5 +/- 2.9 units for RLS and 2.0 +/- 3.1 for ALB. Six patients died (three RLS, there ALB). Three RLS and six ALB patients received intermittent mandatory ventilation or continous positive air pressure after operation. Pulmonary function results were not significantly different between the two groups for any parameter on any day after operation. Results of a randomized trial in human subjects of resuscitation with crystalloid and colloid solutions for acute trauma requiring laparotomy did not reveal significant differences in (1) survival rate, (2) incidence of pulmonary failure, or (3) postoperative pulmonary function.

The incidence, importance, and prophylaxis of acute mountain sickness.

Acute mountain sickness (A.M.S.) and its severe complications, high-altitude pulmonary oedema (H.A.P.O.) and cerebral oedema (C.O.), were studied in 278 unacclimatised hikers at 4243 m altitude at Pheriche in the Himalayas of Nepal. The overall incidence of A.M.S. was 53%, the incidence being increased in the young and in those who flew to 2800 m, climbed fast, and spent fewer nights acclimatising en route. It was unrelated to sex, to previous altitude experience, to the load carried, and to recent respiratory infections. The severity of A.M.S. was inversely related to age (independent of rate of ascent) and the highest altitude attained, and was highly ocrrelated with speed of ascent. There were 7 cases of H.A.P.O. and 5 with the more intractable C.O. and, of these 12, 11 had flown in, 9 had spent only one night at Pheriche, and none were on acetazolamide. 11 required evacuation. Acetazolamide, compared in a double-blind study with a placebo and also compared with no tablets at all, reduced both the incidence and the severity of A.M.S. in those who flew to 2800 m but not in those who hiked up to that altitude. Prevention consists in slow ascent, rapid recognition of warning signs, and prompt descent to avoid progression.

Effects of set, setting, and sedatives, on reaction time.

The effects of sessions, individual characteristics, group behavior, sedative medications, and pharmacological anticipation, on simple visual and auditory reaction time were evaluated with a randomized block design. The project involved 4 separate small groups of 5 to 9 healthy young adults who met 4 times for 9 hr. over 4 mo. and received 4 drug regimens under controlled conditions. Attitudes toward the experiment, which were mainly related to an early fear of potent drugs and late feelings of weariness, markedly affected reaction time. This effect decreased the test-retest reliability of the instrument, hence its sensitivity. Group behavior, subjective feelings attributable to the medications, and pharmacological anticipation, on the other hand, did not seem to have affected psychomotor performance. The effects of sedatives were much more marked and consistent with reaction time than with subjective responses, which primarily represented the influence of anticipation. This dissociation between objective and subjective behavior indicates that the subjects acted according to the drugs which they had taken but felt according to what they believed they had received.

Acute myocardial infarction following wasp sting. Report of two cases and critical survey of the literature.

Over the span of two or three days in August, 1972, in two separate communities in eastern Massachusetts two men, one aged 39, the other 66, each without previous overt heart disease, were stung by wasps. Each went into shock rapidly after an interval of over a half-hour developed chest pain and, later, sequential electrocardiographic changes diagnostic of acute myocardial infarction. Each survived; each had normal electrocardiograms before the sting. Though preexistent coronary artery disease can be excluded in neither, the view is favored that acute myocardial infarction in each was caused by deficient coronary perfusion secondary to anaphylactic shock induced by the wasp stings. An intriguing case was just recently reported58 of a 62-year-old man with previous angina who developed pulmonary edema but no chest pain following wasp sting and went on to show rapidly reversed electrocardiographic changes attributable to subendocardial ischemia or infarction. In a sense, this sequence fills the gap as an intermediate phase between the normal and the two individuals described here who developed pain after anaphylactic shock, then proceeded, perhaps through this phase, to develop transmural infarction.