Subcutaneous perfusion and oxygen during acute severe isovolemic hemodilution in healthy volunteers.

HYPOTHESIS: Acute severe isovolemic anemia (to a hemoglobin [Hb] concentration of 50 g/L) does not decrease subcutaneous wound tissue oxygen tension (PsqO(2)). SETTING: University hospital operating room and inpatient general clinical research center ward. SUBJECTS: Twenty-five healthy, paid volunteers. METHODS: Subcutaneous oxygen tension and subcutaneous temperature (Tsq) were measured continuously during isovolemic hemodilution to an Hb level of 50 g/L. In 14 volunteers (initially well-perfused), "normal" perfusion (Tsq >34.4 degrees C) was achieved by hydration and systemic warming prior to starting isovolemic hemodilution, while in 11 volunteers (perfusion not controlled [PNC]), no attempt was made to control perfusion prior to hemodilution. MAIN OUTCOME MEASURES: Measurements of PsqO(2), Tsq, and relative subcutaneous blood flow (flow index). RESULTS: While PsqO(2), Tsq, and flow index were significantly lower in PNC vs well-perfused subjects at baseline, there was no significant difference between them at the Hb of 50 g/L (nadir). Subcutaneous PO(2) did not decrease significantly in either group. Arterial PO(2) was not different between the groups, and did not change significantly over time; Tsq and flow index increased significantly from baseline to nadir Hb in both groups. CONCLUSIONS: The level of PsqO(2) was maintained at baseline levels during hemodilution to Hb 50 g/L in healthy volunteers, whether they were initially well-perfused or mildly underperfused peripherally. Given the significant increase in Tsq and flow index, this resulted from a compensatory increase in subcutaneous blood flow sufficient to maintain oxygen delivery. Wound healing depends to a large extent on tissue oxygen delivery, and these data suggest that even severe anemia by itself would not be sufficient to impair wound healing. Thus, transfusion of autologous packed red blood cells solely to improve healing in surgical patients with no other indication for transfusion is not supported by these results.

Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans.

BACKGROUND: Controversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia. METHODS: Fifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 +/- 1.2 to 5.2 +/- 0.5 g/dl (mean +/- SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia. RESULTS: During hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5-7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values. CONCLUSION: With acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.

Acute severe isovolemic anemia impairs cognitive function and memory in humans.

BACKGROUND: Erythrocytes are transfused to prevent or treat inadequate oxygen delivery resulting from insufficient hemoglobin concentration. Previous studies failed to find evidence of inadequate systemic oxygen delivery at a hemoglobin concentration of 5 g/dl. However, in those studies, sensitive, specific measures of critical organ function were not used. This study tested the hypothesis that acute severe decreases of hemoglobin concentration alters human cognitive function. METHODS: Nine healthy volunteers, age 29 +/- 5 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dl and again after transfusion of their autologous erythrocytes to return their hemoglobin concentration to 7 g/dl. To control for duration of the experiment, each volunteer also completed the same tests on a separate day, without alteration of hemoglobin, at times of the day approximately equivalent to those on the experimental day. RESULTS: No test showed any change in reaction time or error rate at hemoglobin concentration of 7 g/dl compared with the data at the baseline hemoglobin concentration of 14 g/dl. Reaction time, but not error rate, for horizontal addition and digit-symbol substitution test (DSST) increased at hemoglobin 6 g/dl (mean horizontal addition, 19%; 95% confidence interval [CI], 4-34%; mean DSST, 10%; 95% CI, 4-17%) and further at 5 g/dl (mean horizontal addition, 43%; 95% CI, 6-79%; mean DSST, 18%; 95% CI, 4-31%). Immediate and delayed memory was degraded at hemoglobin 5 g/dl but not at 6 g/dl. Return of hemoglobin to 7 g/dl returned all tests to baseline, except for the DSST, which significantly improved, and returned to baseline the following morning after transfusion of all autologous erythrocytes. CONCLUSION: Acute reduction of hemoglobin concentration to 7 g/dl does not produce detectable changes in human cognitive function. Further reduction of hemoglobin level to 6 and 5 g/dl produces subtle, reversible increases in reaction time and impaired immediate and delayed memory. These are the first prospective data to demonstrate subtle degraded human function with acute anemia of hemoglobin concentrations of 6 and 5 g/dl. This reversibility of these decrements with erythrocyte transfusion suggests that our model can be used to test the efficacy of erythrocytes, oxygen therapeutics, or other treatments for acute anemia.

Fatigue during acute isovolemic anemiain healthy, resting humans.

BACKGROUND: Transfusion guidelines recommend that clinicians assess patients for signs and symptoms of anemia before the transfusion of RBCs. However, studies of signs and symptoms associated with acute isovolemic anemia are limited. The objective of this study was to determine whether acute reduction of Hb concentration to 5 g per dL would result in fatigue, tachycardia, or hypotension in resting, young, healthy, isovolemic humans, and whether changes were reversible with RBC transfusion. STUDY DESIGN AND METHODS: Conscious, resting, healthy adults less than 35 years old (n = 8) underwent acute isovolemic hemodilution to Hb of 5 g per dL and self-scored their energy level at various Hb concentrations. Heart rate and blood pressure were also measured. For controls, measurements of each subject were made during a comparable period of rest without hemodilution. RESULTS: During acute isovolemic hemodilution, energy levels decreased progressively and were lower at Hb of 7, 6, and 5 g per dL than at baseline (p<0.01) or in control sessions (p<0.05). The energy level was lower at Hb 7 g per dL than at 14 ( p = 0.005), lower at Hb 6 g per dL than at 7 (p = 0.01), and lower at Hb 5 g per dL than at 6 (p =0.01). Energy levels rose and were not different from baseline or control levels after transfusion of all autologous RBCs. Similarly, median heart rate increased with hemodilution to Hb of 7, 6, and 5 g per dL and decreased with transfusion of autologous RBCs. Supine blood pressure did not decrease with isovolemic hemodilution. CONCLUSION: In resting, young, healthy humans, acute isovolemic anemia to Hb levels of 7, 6, and 5 g per dL results in decreased self-scored energy levels and in an increase in heart rate but not in hypotension. Changes in energy and heart rate are reversible with the transfusion of autologous RBCs.

Critical oxygen delivery in conscious humans is less than 7.3 ml O2 x kg(-1) x min(-1).

BACKGROUND: The "critical" level of oxygen delivery (DO2) is the value below which DO2 fails to satisfy the metabolic need for oxygen. No prospective data in healthy, conscious humans define this value. The authors reduced DO2 in healthy volunteers in an attempt to determine the critical DO2. METHODS: With Institutional Review Board approval and informed consent, the authors studied eight healthy, conscious volunteers, aged 19-25 yr. Hemodynamic measurements were obtained at steady state before and after profound acute isovolemic hemodilution with 5% albumin and autologous plasma, and again at the reduced hemoglobin concentration after additional reduction of DO2 by an infusion of a beta-adrenergic antagonist, esmolol. RESULTS: Reduction of hemoglobin from 12.5+/-0.8 g/dl to 4.8+/-0.2 g/dl (mean +/- SD) increased heart rate, stroke volume index, and cardiac index, and reduced DO2 (14.0+/-2.9 to 9.9+/-20 ml O2 x kg(-1) x min(-1); all P<0.001). Oxygen consumption (VO2; 3.0+/-0.5 to 3.4+/-0.6 ml O2 x kg(-1) x min(-1); P<0.05) and plasma lactate concentration (0.50+/-0.10 to 0.62+/-0.16 mM; P<0.05; n = 7) increased slightly. Esmolol decreased heart rate, stroke volume index, and cardiac index, and further decreased DO2 (to 7.3+/-1.4 ml O2 x kg(-1) x min(-1); all P<0.01 vs. before esmolol). VO2 (3.2+/-0.6 ml O2 x kg(-1) x min(-1); P>0.05) and plasma lactate (0.66+/-0.14 mM; P>0.05) did not change further. No value of plasma lactate exceeded the normal range. CONCLUSIONS: A decrease in DO2 to 7.3+/-1.4 ml O2 x kg(-1) min(-1) in resting, healthy, conscious humans does not produce evidence of inadequate systemic oxygenation. The critical DO2 in healthy, resting, conscious humans appears to be less than this value.

Autoimmune hemolytic anemia in patients with SCID after T cell-depleted BM and PBSC transplantation.

We report a high incidence (19.5%) of autoimmune hemolytic anemia (AIHA) in 41 patients with SCID who underwent a T cell-depleted haploidentical transplant. Other than infections, AIHA was the most common post-transplant complication in this patient cohort. Clinical characteristics and treatment of eight patients who developed AIHA at a median of 8 months after the first T cell-depleted transplant are presented. All patients had warm-reacting autoantibodies, and two of eight had concurrent cold and warm autoantibodies. Clinical course was most severe in two patients who had cold and warm autoantibodies. Five patients received specific therapy for AIHA. Successful taper off immunosuppressive therapy for AIHA coincided with T cell reconstitution. Delayed reconstitution of T cell immunity, due to T cell depletion, immunosuppressive conditioning and CsA, as well as paucity of regulatory T cells, are the likely explanations for the occurrence of AIHA in our patient cohort. Screening of the population at risk may prevent morbidity and mortality from AIHA.

Autologous blood use in percutaneous nephrolithotomy.

OBJECTIVES: Preoperative autologous blood (AUB) donation has decreased patient exposure to allogenic blood (ALB) products and associated infectious risk. The risk of contracting hepatitis C and human immunodeficiency virus is 1 in 103,000 and 1 in 678,000, respectively, after receiving 1 U ALB. Elective surgical procedures require surgeons to offer preoperative AUB donation in California. Unused AUB is discarded. We report our use of AUB obtained for percutaneous nephrolithotomy. METHODS: A retrospective study of 144 consecutive patients who underwent 193 percutaneous nephrolithotomies between January 1994 and April 1998 at one of four teaching hospitals at the University of California, San Francisco was performed. Preoperative AUB donation, transfusion rates, hemoglobin levels, blood use, and costs were analyzed. RESULTS: Ninety-six units of blood were collected from 63 patients (44%) and were available for 70 procedures (36%). The overall transfusion rate per procedure was 7%, with 13 patients receiving a total of 24 U, 7 AUB and 17 ALB. Eighty-nine units (92.7%) of AUB were discarded, and the transfusion rate in donors and nondonors was similar. There was no significant difference in preoperative hemoglobin or operative blood loss between donors and nondonors. The 13 transfused patients had a lower preoperative hemoglobin ( 11.5 versus 12.8 g/dL; P = 0.029) and higher operative blood loss as measured by hemoglobin level (3.2 versus 1.6 g/dL; P <0.001). Blood bank charges for ALB and AUB were $ 119/U and $244 to $498/U, respectively, depending on transportation and thawing charges. CONCLUSIONS: Routine preoperative blood donation adds substantial cost for minimal benefit, given the low infectious risk of ALB and the two- to fourfold higher cost of AUB. In our series, women had an increased incidence of blood transfusion compared with men. AUB donation may provide peace of mind but is rarely used and is discarded 93% of the time.

Hepatitis after liver transplantation: the role of the known and unknown viruses.

This study was designed to determine the cause of posttransplantation hepatitis in patients undergoing transplantation for liver disease of nonviral cause; the role of acquired hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis G virus (HGV) in posttransplantation hepatitis; and the course of posttransplantation hepatitis of unknown cause. Two hundred forty-three patients underwent transplantation for nonviral liver diseases (mean age, 48 years; 103 men, 140 women). Serological and virological assays for HBV and HCV were performed pretransplantation to exclude preexisting infection and posttransplantation to investigate the cause of posttransplantation hepatitis. Histology was graded on all available biopsy specimens; posttransplantation hepatitis was assessable in 150 patients. Posttransplantation hepatitis was present in 29% (44 of 150) of the patients after a median follow-up of 47 months (range, 1 to 101 months). Actuarial survival was significantly lower in patients with posttransplantation hepatitis compared with patients without (71% v 89% at 5-year follow-up; P = .03). HCV and HBV were identified posttransplantation in 14% and 9% of patients with hepatitis, respectively. After the exclusion of HCV and HBV infection, 22% (33 of 150) of the patients had posttransplantation hepatitis of unknown cause. HGV was present in 58% of these patients, but HGV was equally prevalent in patients without posttransplantation hepatitis. When patients with HBV and HCV were excluded, there was no difference in survival between patients with posttransplantation hepatitis compared with patients without (P = .08, log-rank test). Posttransplantation hepatitis was present in approximately 30% of the patients undergoing transplantation for nonviral diseases, with a median follow-up of 47 months. Known hepatitis viruses (HBV, HCV) were present in one fourth of the patients with posttransplantation hepatitis; 22% (33 of 150) of the patients had hepatitis of unknown cause, suggesting that other, as yet undiscovered, hepatitis viruses may exist.

Human cardiovascular and metabolic response to acute, severe isovolemic anemia.

CONTEXT: Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. OBJECTIVE: To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. DESIGN: Before and after interventional study. SETTING: Academic tertiary care medical center. PARTICIPANTS: Conscious healthy patients (n =11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). INTERVENTIONS: Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. MAIN OUTCOME MEASURES: "Critical" oxygen delivery (TO2) as assessed by oxygen consumption (VO2), plasma lactate concentration, and ST changes on electrocardiogram. RESULTS: Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO2 and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: VO2 increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O2 x kg(-1) x min[-1]) to 3.42 (0.54) mL O2 x kg(-1) x min(-1) (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L; P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. CONCLUSIONS: Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO2, as assessed by lack of change of VO2 and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.

The sensitive detection and quantitation of antibody to HCV by using a microsphere-based immunoassay and flow cytometry.

Antibody to HCV core and NS3 was quantified by using a microsphere immunoassay and flow cytometry. Antibody to core and NS3 was elevated in the 85 seropositive blood donors tested. The amount of either antibody varied over two logs although greater variation was seen with the antibody to NS3 than was seen with antibody to core. In three documented acute HCV cases, the microsphere assay detected antibody prior to antibody detection using the reference methods. Twenty donor samples were indeterminate by the reference methods: 45% of these were indeterminate with the microsphere assay while 25% were negative and 30% were positive. As compared to enzyme immunoassay the microsphere assay showed a 5-fold increase in sensitivity. The microsphere assay demonstrated increased sensitivity for the quantification of specific antibody to HCV core and NS3 and was useful in resolving a significant proportion of indeterminate samples.

Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation.

To examine the prevalence of hepatitis G virus (HGV) in end-stage liver disease of unknown cause and the role of HGV infection in posttransplantation hepatitis, we studied 46 patients undergoing liver transplantation (mean age, 50 years; M:F, 18:28) with cryptogenic cirrhosis. HGV RNA was detected by polymerase chain reaction (PCR) and was quantified by a branched DNA (bDNA) assay. The prevalence of HGV RNA was determined in samples collected before and after liver transplantation and was found to be 22% and 67%, respectively. We evaluated the prevalence of posttransplantation hepatitis in 25 patients, 16 of whom were HGV-positive and 9 were HGV-negative. The proportion of patients with hepatitis was not significantly different in the two groups (38% in HGV-positive and 22% in HGV-negative patients). The median histological scores were significantly higher in liver biopsies from patients with HGV infection than in those without HGV infection (2 [range, 0-14] and 1 [range, 0-3]; P = .01), but the histological scores were low overall. The duration of follow-up was similar in the two groups. HGV RNA levels were not correlated with the severity of liver disease based on histological score (r = -.08). Graft survival and patient survival were not significantly different. We concluded that liver disease was frequent (32%) after transplantation in patients with a pretransplantation diagnosis of cryptogenic cirrhosis, although the disease was generally mild. Although HGV RNA was demonstrable in the majority (67%) of patients after transplantation, there was no relationship between the presence of HGV RNA and the presence of posttransplantation liver disease. The finding of posttransplantation hepatitis in the absence of known viruses (A-G), suggests that other, as-yet-unidentified viruses may be important.

Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics.

BACKGROUND: Recombinant human hemoglobin (OptroD; rHb1.1) is a genetically engineered protein produced in Escherichia coli. The two alpha-globin polypeptides are genetically joined, resulting in a stable tetramer that does not dissociate into dimers or monomers. Historically, infusion in humans of acellular hemoglobin preparations has resulted in renal toxicity. This study was performed to evaluate the safety and pharmacokinetics of rHb1.1 when infused in humans. METHODS: After giving informed consent, 48 healthy male volunteers were randomly assigned to receive either 0.015-0.32 g/kg 5% rHb1.1 (n = 34) or an equivalent amount of 5% human serum albumin (HSA; n = 14) infused intravenously over 0.8-1.9 h. Serum creatinine, creatinine clearance, urine N-acetyl-beta-glucosaminidase, and serum rHb1.1 concentrations were measured before and at timed intervals after infusion. RESULTS: Postinfusion urine N-acetyl-beta-glucosaminidase activity did not exceed preinfusion values at any interval in either group. Serum creatinine did not differ from preinfusion values at 1 day, 2-3 days, or 7 days after infusion for either group. Creatinine clearance increased significantly for the HSA group 12 h after infusion (138 +/- 16 ml/min, means +/- SE) and in the rHb1.1 group 1 day after infusion (112 +/- 5 ml/min; P < 0.05). Values for creatinine clearance did not differ from preinfusion values for either group at any other postinfusion interval; serum creatinine and creatinine clearance did not differ between groups at any time. The amount of hemoglobin excreted in the urine did not exceed approximately 0.04% of the administered rHb1.1 dose in any volunteer. Plasma clearance of rHb1.1 decreased and half-life increased as a function of increasing plasma concentration (e.g., the half-life was 2.8 h at a plasma concentration of 0.5 mg/ml and 12 h at 5 mg/ml). The incidence of gastrointestinal symptoms, fever, and chills was greater after infusion of rHb1.1 than after HSA (P < 0.05). CONCLUSIONS: No evidence for rHb1.1-mediated nephrotoxicity was observed in volunteers given doses of rHb1.1 as large as 0.32 g/kg. Because the clearance of rHb1.1 varies inversely with its concentration, additional studies with larger doses are necessary to determine the half-life expected in clinical use. Administration of rHb1.1 to conscious humans is associated with some side effects, such as gastrointestinal upset, fever, chills, headache, and backache.

What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah's Witnesses.

BACKGROUND: A transfusion threshold of 7 g per dL (70 g/L) of hemoglobin has been proposed for patients, although scant human data are available to support this recommendation. STUDY DESIGN AND METHODS: The medical community's experience with Jehovah's Witnesses was examined, in order to assess the lowest tolerable hemoglobin concentration and the lower transfusion threshold of 7 g per dL (70 g/L) of hemoglobin. A MEDLINE search was conducted to capture medical and surgical reports involving Jehovah's Witnesses from 1970 through early 1993. RESULTS: Sixty-one reports of untransfused Jehovah's Witnesses with hemoglobin concentrations < or = 8 g per dL (80 g/L) or hematocrits < or = 24 percent (0.24) were identified. Of 50 reported deaths, 23, as stated in the original reports, were primarily due to anemia. Except for three patients who died after cardiac surgery, all patients whose deaths were attributed to anemia died with hemoglobin concentrations < or = 5 g per dL (50 g/L). Twenty-five survivors were reported with hemoglobin < or = 5 g per dL (50 g/L). CONCLUSION: These data have significant limitations but suggest that survival, without transfusion, is possible at low hemoglobin concentrations, while mortality with an unknown incidence is encountered at hemoglobin concentrations below 5 g per dL (50 g/L).