Harriet W. Hopf

WOUND HEALING AND WOUND INFECTION: What Surgeons and Anesthesiologists Can Do

Wound healing can be enhanced and wound infections prevented, often by simple, inexpensive, readily available means. Preoperative evaluation for impediments to healing, such as malnutrition, vasoconstriction, hyperglycemia, and steroid use, allows correction prior to operation. Intraoperatively, the surgeon should concentrate on surgical technique, appropriate antibiotic use, and prevention of vasoconstriction (volume, warming). Postoperatively, the focus should be on prevention of vasoconstriction through pain relief, warming, and adequate volume resuscitation and on maintaining nutrition and normoglycemia. These approaches apply as well to chronic wounds. Additionally, maintenance of a moist environment, correction of local vasospasm with sympathetic blockade or warming, and stimulation of angiogenesis through aggressive debridement or hyperbaric oxygen therapy enhance healing of chronic wounds.

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.

Hyperoxia and angiogenesis

We hypothesized that tissue hyperoxia would enhance and hypoxia inhibit neovascularization in a wound model. Therefore, we used female Swiss‐Webster mice to examine the influence of differential oxygen treatment on angiogenesis. One milliliter plugs of Matrigel®, a mixture of matrix proteins that supports but does not itself elicit angiogenesis, were injected subcutaneously into the mice. Matrigel® was used without additive or with added vascular endothelial growth factor (VEGF) or anti‐VEGF antibody. Animals were maintained in hypoxic, normoxic, or one of four hyperoxic environments: hypoxia—13 percent oxygen at 1 atmosphere absolute (ATA); normoxia—21 percent oxygen at 1 ATA; hyperoxia—(groups a–d) 100 percent oxygen for 90 minutes twice daily at the following pressures: Group a, 1 ATA; Group b, 2 ATA; Group c, 2.5 ATA; Group d, 3.0 ATA. Subcutaneous oxygen tension was measured in all groups. The Matrigel® was removed 7 days after implantation. Sections were graded microscopically for the extent of neovascularization. Angiogenesis was significantly greater in all hyperoxic groups and significantly less in the hypoxic group compared with room air‐exposed controls. Anti‐VEGF antibody abrogated the angiogenic effect of both VEGF and increased oxygen tension. We conclude that angiogenesis is proportional to ambient pO2 over a wide range. This confirms the clinical impression that angiogenesis requires oxygen. Intermittent oxygen exposure can satisfy the need for oxygen in ischemic tissue.

Fresh Blood and Aged Stored Blood Are Equally Efficacious in Immediately Reversing Anemia-induced Brain Oxygenation Deficits in Humans

Background:Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h. Methods:Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit–symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h (“fresh”) or 3 weeks (“stored”) to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion. Results:Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion–induced DSST improvement did not differ between groups (P = 0.96). Conclusion:Erythrocytes stored for 3 weeks are as efficacious as are erythrocytes stored for 3.5 h in reversing the neurocognitive deficit of acute anemia. Requiring fresh rather than stored erythrocytes for augmentation of oxygen delivery does not seem warranted.

Oxygen Reverses Deficits of Cognitive Function and Memory and Increased Heart Rate Induced by Acute Severe Isovolemic Anemia

Background Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2–3 g/dl and thus reverse the effects of acute anemia. Methods Thirty-one healthy volunteers, aged 28 ± 4 yr (mean ± SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 ± 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test. Results Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 ± 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 ± 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia. Conclusion The authors confirmed that acute isovolemic anemia subtly slows human reaction time, degrades memory, increases heart rate, and decreases energy level. The findings of this study support the hypothesis that increasing Pao2 to 350 mmHg or greater by breathing oxygen reverses all of these effects of acute anemia except for decreased energy.

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

BackgroundControversy 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. MethodsFifty-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. ResultsDuring 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. ConclusionWith 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.

Centrally and locally mediated thermoregulatory responses alter subcutaneous oxygen tension

Mild perianesthetic hypothermia decreases resistance to infections. Decreased resistance likely results in part from direct immune inhibition. However, decreased tissue oxygen partial pressure also decreases resistance to infection by impairing oxidative killing by neutrophils and collagen deposition. Thermoregulatory vasoconstriction decreases skin blood flow and may also decrease subcutaneous tissue oxygen tension. Accordingly, we determined the influence of centrally and locally mediated thermoregulatory vasomotion on subcutaneous oxygen tension. We also compared subcutaneous oxygen tension to other potential markers of tissue perfusion: laser Doppler flowmetry and transcutaneous oxygen tension. Arterial oxygen tension was maintained near 325 mm Hg in five volunteers. Control subcutaneous oxygen tension values were recorded after 1 hour of euthermia (no sweating or vasoconstriction). Volunteers were then cooled with a circulating‐water mattress positioned under the trunk and legs. After 1.5 hours of cooling sufficient to produce shivering, the right upper arm was covered for 1 hour with a small circulating water blanket set to 40° C while systemic cooling continued. The volunteers were then systematically warmed to produce sweating, and the right arm was locally cooled. There was no correlation among laser Doppler flowmetry, transcutaneous oxygen tension, and subcutaneous oxygen tension. Systemic cooling significantly decreased subcutaneous oxygen tension, but subcutaneous oxygen tension in the right arm returned to control values during local heating. Systemic warming significantly increased subcutaneous oxygen tension, and 1 hour of local cooling failed to fully reverse the increase. These data indicate that thermoregulatory vasoconstriction significantly decreases tissue oxygen availability. Decreased subcutaneous oxygen tension may be one mechanism by which mild perianesthetic hypothermia facilitates development of surgical wound infections.

Guidelines for the treatment of arterial insufficiency ulcers

1. Co-chaired panel 2. University of Utah, Salt Lake City, UT 3. University of Texas, San Antonio, TX 4. Sinai Hospital/Johns Hopkins Medical Institutions, Baltimore, MD 5. GKT School of Medicine, King’s College, London, UK 6. University of Texas Health Science Center at Houston, TX 7. Sequoia Hospital, Redwood City, CA 8. Maricopa Medical Center, Phoenix, AZ 9. Tufts-New England Medical Center, Boston, MA 10. Southampton University Hospitals Trust NHS, Southampton, UK 11. Penrose–St. Francis Health Services, Colorado Springs, CO 12. Beverly Surgical Associates, Beverly, MA 13. Saint Francis Memorial Hospital, San Francisco, CA 14. Northbay Center for Wound Care, Vacaville, CA, and 15. University of California, San Francisco, CA

Acute isovolemic anemia impairs central processing as determined by P300 latency

OBJECTIVE Acute anemia slows the responses to clinical tests of cognitive function. We tested the hypothesis that these slowed responses during acute severe isovolemic anemia in healthy unmedicated humans result from impaired central processing. METHODS A blinded operator measured the latency of the P300 peak in nine healthy volunteers at each volunteers baseline hemoglobin concentration (Hb), and again after isovolemic hemodilution to Hb 5 g/dL. At both Hb concentrations, the P300 latency was measured twice: with the blinded subject breathing air or 100% oxygen, administered in random order. RESULTS Anemia increased P300 latency significantly from baseline values (P < 0.05). Breathing oxygen during induced anemia resulted in a P300 latency not different from that at baseline when breathing air (P = 0.5) or oxygen (P = 0.8). CONCLUSIONS Impaired central processing is, at least in part, responsible for the slowed responses and deficits of cognitive function that occur during acute isovolemic anemia at Hb 5-6 g/dL. SIGNIFICANCE The P300 latency appears to be a potential measure of inadequate central oxygenation. In healthy young adults with acute anemia, erythrocytes should be transfused to produce Hb>5-6 g/dL. As a temporizing measure, administration of oxygen can reverse the cognitive deficits and impaired central processing associated with acute anemia.

Local radiant heating increases subcutaneous oxygen tension

BACKGROUND We evaluated a novel bandage that incorporates a thermostatically controlled radiant heater. We first determined optimal bandage temperature, based on increases in subcutaneous oxygen tension, a measure correlating well with resistance to infection and wound strength. We then tested the hypothesis that prolonged radiant heating would increase collagen deposition in experimental thigh wounds. METHODS The experimental bandages were positioned on the anterior thigh of 8 volunteers, and heated for 2 hours at 38 degrees C, 42 degrees C, or 46 degrees C, in a random order. Subcutaneous oxygen tension under the bandage was recorded from an electrode positioned within a subcutaneous tonometer. We studied 10 volunteers in the second protocol. For 1 week, the experimental bandage was continuously applied to one thigh, and heated to 38 degrees C using a 2-hour on/off cycle. On the alternate week, a standard gauze bandage was applied to the contralateral thigh. Treatment order was randomly assigned. Wound collagen deposition under each bandage was evaluated with subcutaneous polytetrafluoroethylene tubes, which were removed and assayed for hydroxyproline on the eighth day. Data are presented as means +/- SDs. RESULTS Skin temperature during heating ranged from 36 degrees C to 37.5 degrees C. Oxygen tension increased approximately 50% during heating, but the increase was comparable at the three tested temperatures. Even after heating was discontinued, subcutaneous oxygen tension remained elevated for the remaining 3 study hours. Collagen deposition after 1 week of active heating was 3.4 +/- 1.0 microg/ cm. After 1 week of control treatment, collagen deposition was 3.2 +/- 1.1 microg/cm (P = not significant). CONCLUSIONS Our data suggest that radiant heating at 38 degrees C significantly increases subcutaneous oxygen tension, and presumably resistance to infection. However, prolonged heating at this temperature does not increase wound collagen deposition.