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Tissue Oxygenation, , and in Relation to Wound Healing in Surgical Patients

KENT JONSSON, M.D., PH.D.,* J. ARTHUR JENSEN, M.D., WILLIAM H. GOODSON, III, M.D., F.A.C.S., HEINZ SCHEUENSTUHL, A.B., JUDITH WEST, R.N., M.N., HARRIET WILLIAMS HOPF, M.D., and THOMAS K. HUNT, M.D., F.A.C.S., F.R.C.S. (GLASG)

Oxygen tension and collagen deposition were measured in stan- From the Department of Surgery, University of California, dardized, subcutaneous wounds in 33 postoperative surgical pa- San Francisco, California tients. Pertinent clinical and wound parameters were analyzed by Pearson's correlation test and sequential linear regression analysis. Collagen deposition was directly and significantly pro- portional to wound tension and measures of perfusion. There were no significant correlations with , estimated as one of the rationalizations.'0"' Therefore many sur- loss, length of operation, smoking, age, weight, sex, or geons find confusing the considerable experimental evi- output. This study in humans confirms animal experiments showing that collagen deposition and tensile strength in wounds dence that low levels are compatible with are limited by perfusion and tissue oxygen tension. It appears normal healing, and remain reluctant to tolerate even unnecessary to maintain hemoglobin at normal levels to support moderate anemia in postoperative patients.12-18 repair, provided that peripheral perfusion can be maintained at Unfortunately the anemia question diverts attention a high level in compensation for anemia. These circumstances the greater significance of experimental data that reflect the fact that although oxygen is essential to many aspects from of healing, and must be delivered at adequate partial pressures, link healing closely to arterial and tissue oxygen tension reparative tissue consumes relatively little of it. and far less closely to arterial oxygen content.3 4,6 These data together with a century ofsurgical experience suggest URGEONS HAVE LONG recognized that ischemic that the rate ofperfusion oftissue is particularly important tissues heal poorly and are easily infected. Recently in ensuring repair and furthermore that rapid perfusion that observation has been refined by experiments of hyperoxic blood can not only overcome the effects of in animals showing that arterial retards repair significant anemia, but can accelerate healing beyond even when present as an isolated variable. 1-6 Furthermore usual expectations. most components ofhealing exceed normal expectations The present study was designed to measure oxygen ten- during moderate tissue hyperoxia.'-6 Anemia would seem, sion and perfusion in wounds of surgical patients and to therefore, to be inimical to healing, and for many years correlate them to the rate of collagen deposition, which surgeons and anesthesiologists have assumed so, largely is the major determinant of adequacy of repair in closed on the basis of marginal evidence in which nutritional wounds. The goals were (1) to test the validity for humans and blood volume issues were confused with simple, nor- of prior observations in animals in which collagen de- movolemic anemia.79 Some modern textbooks ofsurgery position in wounds was proportional to arterial oxygen still recommend that hemoglobin levels be maintained at tension over a broad range extending above and below or above 10 g/dL, with protection ofwound healing given normal levels, and (2) to determine the degree of anemia that can be tolerated with respect to healing in human patients. Supported by NIH GM 27345. If the relationship between oxygenation and healing * Present address, University of Lund, Department of Surgery, Malmo found in animals can be proved to apply to man, new General Hospital, 21401 Malmo, Sweden. perspectives open on support of wound healing. For in- Address reprint requests to T. K. Hunt, M.D., Department ofSurgery, such as 513 Parnassus Ave., University ofCalifornia, San Francisco, CA 94143- stance vasodilating agents alpha-adrenergic 0522. blockers, nitroprusside, endothelin, etc., could become Accepted for publication February 8, 1991. useful for treatment of endangered wounds. Blood trans-

605 606 JONSSON AND OTHERS Ann. Surg. * November 1991 fusions might be avoided, and a rationale might be con- they were to remain in hospital long enough to complete structed for hyperbaric therapy. the study and were free ofobvious impediments to healing such as , malnutrition, uremia, and Cushing's Methods syndrome. Pertinent clinical features were recorded (Ta- Wound-tissue oxygen tension (PSCO2) and collagen de- ble 1). position were measured in immediately adjacent, stan- At the end of each operation, a gas-sterilized, Luer- dardized experimental wounds in 33 surgical patients, 23 hubbed Silastic catheter (1 mm outer diameter, 0.8 mm women and 10 men (Table 1). Patients were solicited if inner diameter, 15 cm length) was threaded from caudad

TABLE 1. Patients Ranked in Ascending Order ofCollagen Deposition Collagen Ag/cm Operation Length Blood Loss Pre-/Postoperative PscO2 Perfusion Patient Operation (min) (ml) Age HCT (air, max) Score 5 Days 7 Days I Perforated ulcer, 105 50 74 56/57 51, 51 0 0.36 cholecystectomy 2 Modified radical 165 400 57 39/33 48, 53 1 0.40 0.74 mastectomy 3 Repair gastric staple line; 330 300 51 34/29 43, 47 1 0.70 0.53 ventral herniorrhaphy 4 Repair vesicovaginal fistula 480 1050 42 45/30 48, 53 1 0.46 1.45 5 Intestinal fistulectomy 420 1000 56 30/31 41, 53 2 2.47 2.15 6 Breast reconstruction; 230 200 57 40/40 26, 53 1 2.09 3.04 ventral herniorrhaphy 7 Small bowel resection 300 500 39 43/34 44, 53 1 2.26 2.78 (Crohn's disease) 8 Hepatic lobectomy 210 2600 60 44/49 52, 63 2 2.36 9 Femoral herniorrhaphy 110 100 46 43/37 43, 89 3 2.55 2.95 10 Ventral herniorrhaphy 260 300 68 44/37 44, 64 3 2.78 3.55 11 Modified radical 180 300 50 37/37 41, 73 2 2.90 3.54 mastectomy 12 Lyse adhesions, excision of 180 350 60 38/33 52, 88 3 3.00 chylous cyst 13 Angelchik prostesis 215 350 73 35/33 38, 54 3 3.16 3.30 (hiatus hernia) 14 Modified radical 165 800 53 40/27 48, 60 2 1.04 3.53 mastectomy 15 Gastric bypass 255 250 52 43/37 44, 63 3 1.94 4.67 16 Right hemicolectomy 135 100 81 39/34 52, 64 2 2.88 3.73 17 Bowel resection 210 300 75 22/28 47, 52 1 3.17 3.73 (intestinal gangrene) 18 Ventral herniorrhaphy 180 100 34 42/37 34, 68 3 3.55 3.93 19 Ventral herniorrhaphy 70 20 54 45/39 36, 54 3 3.09 4.17 20 Ventral herniorrhaphy 250 500 56 42/31 35, 48 3 3.23 4.25 21 Inguinal herniorrhaphy 110 30 46 40/40 38, 68 2 3.42 4.00 22 Parathyroidectomy 270 100 33 24/25 57, 85 3 3.61 4.31 23 Hemicolectomy 240 650 34 48/43 57, 81 3 4.11 0.82 24 Gastric resection 210 150 69 42/31 47, 73 3 6.51 2.12 25 Soleus flap 170 50 42 18/16 60, 109 3 4.53 4.03 26 Oophorectomy 180 500 38 43/37 50, 98 3 4.74 27 Modified radical 110 50 52 43/33 42, 118 3 4.67 5.18 mastectomy 28 Modified radical 170 200 69 44/36 44, 87 3 3.21 7.63 mastectomy 29 Ileostomy takedown 190 200 64 34/35 28, 44 3 6.33 4.74 30 Gastric resection, 170 150 71 34/34 43, 83 3 5.11 6.66 Roux-en-Y 31 Modified radical 180 200 43 38/40 56, 97 3 7.01 mastectomy 32 Common duct 430 1500 25 40/33 47,91 3 5.42 11.55 exploration 33 Modified radical 225 250 53 41/41 51,90 2 7.37 13.65 mastectomy Total Mean ± SD 220 ± 120 414 ± 514 54 ± 14 39 ± 7/35 ± 7 3.3 ± 1.7 4.1 ± 2.8 Range 70-480 50-2600 25-81 18-56/16-57 0.4-7.4 0.4-13.7 Vol. 214 - No. 5 TISSUE OXYGENATION, ANEMIA, PERFUSION, AND WOUND HEALING 607 to cephalad subcutaneously on the lateral aspect of the obtained. Blood was drawn for arterial gas measurement upper arm by means of an 18-gauge, 10-cm needle (Ab- if clinically indicated. bocath T, Abbott Hospital, Inc., North Chicago, IL) so The corresponding values of PwO2 and arterial P02 that 7 cm remained in the subcutaneous position. Two (Pao2) were compared with the curve (Fig. 1) constructed pieces of porous (extruded) polytetrafluoroethylene from data obtained in similar postoperative patients who (ePTFE) tubing (6 cm long, 1 mm OD, pore size 90-120 were considered to be well perfused.20 When tissue hyp- ,Mm) (Gore-Tex, W. L. Gore & Assoc., Flagstaff, AZ) were oxia relative to Pao2 was found, supplemental fluid (250- similarly placed parallel to and approximately two and 500 mL 0.9% saline) above the ongoing rate was given four centimeters laterally from the Silastic tube. A single rapidly and PCO2 was remeasured. IfPsO2 increased dur- piece of 10- X 12-cm adherent plastic film was the only ing the supplemental infusion, more fluid was given until dressing. there was no further increase or until PwO2 rose into the Wound-tissue oxygen tension was measured 2 to 6 normal range. All patients breathed supplemental oxygen hours after the operation and daily thereafter. A reference by nasal prongs at 4 L/min for approximately 12 hours (silver/silver chloride) electrode was inserted through a per day during the first 3 postoperative days. stopcock at the hubbed end of the Silastic catheter. Air The ePTFE tubes were removed on the fifth and seventh was displaced with saline. A square-tipped, platinum nee- days and were frozen immediately.2' For assay they were dle electrode (Diamond Electrotech, Inc., Ann Arbor, MI) twice washed briefly in water to remove soluble , was inserted at the opposite end, and the sensor tip was specifically complement, which contains some hydroxy- positioned subcutaneously.'9 Twenty minutes was allowed proline, and hydrolyzed for 18 hours in 6 N hydrochloric to reach thermal and gaseous equilibrium, and a baseline at 130 C. Total hydroxyproline content was measured was defined when the readings varied less than 2 mm Hg by a modification of the automated method of Grant.22 for 10 minutes. Supplemental oxygen was then given by Results are expressed as micrograms ofcollagen per cen- a plastic facemask at 5 L/min (fraction ofinspired oxygen timeter of ePTFE tubing by multiplying hydroxyproline [FIO2] 0.6-0.7), and PCO2 was recorded at 5-minute in- by 6.94. tervals for at least 20 minutes or until stable readings were This study was approved by the Committee on Human Research of the University of California, San Francisco, and informed consent and written permission were oh tained from all subjects.

Data Analysis 160 0 Only the analysis of the first 3 days of oximetry data 140 are shown because these days are the most influential for 0 collagen deposition,3'6 and because the differences in tissue 120 0 oximetry data between patients lessened after the third day as patients recovered. oflater data tends to 0~ 100 0 * 0 differences found in the first few 0 obscure the important 0 C,, days. 0 C,, 80 * *. Pertinent clinical and laboratory data are shown in Ta- *' *l ble 1. The patients are listed in order ofincreasing collagen 60 r;0 *;.0 .e 0 0 W deposition. 40 The tissue oxygen data were analyzed in several ways. First a "perfusion score" based on the was 20 calculated. On each day of observation, patients were classified as well perfused and given a score of 1 if their I LI I I I P.CO2 rose significantly (20% or more) in response to 20 60 100 140 180 220 260 300 oxygen. A score of 0 was given for a lesser re- ARTERIAL P02 (torr) sponse. The meaning of this score rests on the fact that tissue oxygen tension can be significantly elevated by in- MG. 1. Tissue oxygen tensions previously measured by the current method ifthe extraction ratio of in a group of patients who had abdominal surgery, uneventful postop- creasing FIO2 values only oxygen erative convalescence, no signs of hemodynamic instability, and urine the tissue is small and hence perfusion is excellent. Healing output greater than 49 mL/hr, and whose tissue Po2 rose in response to tissue constantly extracts only about 0.7 mL oxygen per breathing oxygen and had a measured change in arterial P02.? The tissue mL oxygen tension at any given arterial Po2 in the patients recorded in this 100 ofperfusing blood when perfusion is normal.23'24 figure was lower than that found in normal, unoperated volunteers. Oxygen delivered in plasma alone (0.3 mL/dL mm Hg) 608 JONSSON AND OTHERS Ann. Surg. * November 1991 81 Collagen pzg/cm 71

6

5. I 4.

3'

I 2

1.

0- 1 2 3 Perfusion score

FIG. 2. The relationship between collagen accumulation on day 5 (gg/cm ePTFE tubing) and perfusion score. Significant difference, p < 0.05 between patients with perfusion scores I and 3, Student's t test. Data on day 7 were similar. begins to satisfy that need when Pao2 rises toward 300 In a second analysis, we averaged the maximum PscO2 mm Hg. Thus, as shown in Figure 1, Ps,O2 in well-perfused values (PAO2 max), developed while patients breathed ox- patients continues to rise as Pao2 rises even to levels above ygen during measurements on days 0, 1, and 2. This single, full saturation of hemoglobin. For the same reason, Pao2 direct measurement represents the actual P02 levels and Ps,O2 reach a linear relationship when Pao2 reaches reached in the ePTFE wounds and also sums up the pa- about 300 mm Hg.20 Conversely when perfusion dimin- tients' perfusion and cardiopulmonary function because ishes, the extraction ratio of oxygen rises, more hemoglo- PSC02 is continuously proportional to Pao2 only as the bin-bound oxygen is consumed, and PscO2 decreases and degree of perfusion allows, and Pao2 can be raised by becomes increasingly less responsive to changes in Pao2.23 oxygen administration only to the degree that cardiopul- Twenty per cent was arbitrarily chosen as the minimum monary function allows. Its relationship to collagen de- significant change because the PscO2 measurements are position is shown in Table 1 and Figure 3. reproducible to approximately ±5% to 10%. Correlations among the clinical parameters listed in Given these operational definitions and using data pro- Table 1, the collagen accumulations, the perfusion scores, vided by Gottrup et al.,23 the point at which an average and PscO2 maximums were sought by Pearson's correla- patient would convert from "well perfused" (score of 1) tion test. These correlations were then ranked by sequen- to "poorly perfused" (score of 0) is calculated to be at tial linear regression analysis. approximately 50% ofthe normal subcutaneous perfusion, as measured by these techniques in dogs23 and in human Results volunteers with normal hematocrit at room temperature.25 Collagen accumulation on day 7 (mean, 4.14) was 20% For analysis the scores on days 0, 1, and 2 were added, higher than on day 5 (mean, 3.32) (p < 0.01, Wilcoxon). giving possible scores of 0 to 3 (Table 1 and Fig. 2). The Two of the oximetric parameters, Ps,O2 max (during perfusion score ignores the absolute value of PCO2 and supplemental oxygen breathing) and perfusion score, may falsely classify patients whose arterial hemoglobin is emerged as predictors of collagen accumulation at both significantly unsaturated on breathing air. Only 5 of the 5 and 7 days (Figs. 2 and 3). Postoperative hematocrit 33 patients, however, are likely to have been misclassified was correlated to neither collagen deposition (p = 0.20) on this basis (patients 10, 13, 19, 20, and 29). (Fig. 4) nor PscO2 at either day 5 or 7. Length ofoperation, Vol. 214 * No. 5 TISSUE OXYGENATION, ANEMIA, PERFUSION, AND WOUND HEALING 609 Collagen pg/cm

9

#

# 5 # # # 4

3, * # #, I #

2-

# # 6 0-

40 50 60 70 60 90 100 110 120 MaxpO2 mmHg

FIG. 3. The regression line reflects the relation between collagen accumulation on day 5 (,ug/cm ePTFE tubing) and Po2 max mm Hg. Data on day 7 were similar. weight, sex, urine output, estimated blood loss, and vol- There are statistically insignificant trends toward cor- ume oftransfused blood bore no correlation to perfusion relations with smoking and age. No trend developed for score, maximum PCO2, or collagen deposition. any other clinical criterion. No patient had Sequential linear regression analysis of collagen accu- or microcytosis. One patient (patient 25) had severe sickle mulation using these predictors (in the Minitab computing anemia. No patient developed an acid-base or elec- package) led to several regression equations. Those per- trolyte disorder. The core temperature range of these pa- tinent to PscO2 max and perfusion score are: tients was 37 to 39 C rectally and 36.5 to 38 C orally. For max PscO2 Discussion Collagen (day 5) = -0.17 + (0.05 ± 0.01) X (max PscO2) (p < 0.01) The ePTFE model employed has been extensively tested Collagen (day 7) = -1.10 + (0.08 ± 0.02) X (max PscO2) in animals and man. It measures collagen deposition, (p <0.01) which is the major determinant of tensile strength in pri- For perfusion score: marily closed wounds.2 2628 Insertion ofthe ePTFE tube Collagen (day 5) = 0.49 + (1.20 0.33) X (perfusion through tissue creates a test wound, and the healing pro- < 0.00 score) (p 1) cess subsequently fills its pores by migration of cells, = 1.23 + X Collagen (day 7) (1.27 0.54) (perfusion growth of new vessels, and deposition of collagen. When < score) (p 0.03) the tube is removed, it samples the healing tissue by re- The correlation coefficients between collagen and PCO2 taining only that tissue that has penetrated its pores. It max at days 5 and 7 were both 0.51. With regard to col- represents a modification of similar methods (wire mesh lagen and perfusion score, they were 0.57 at day 5 and cylinders, cotton sponges, cellulose sponges, polyvinyl 0.40 at day 7. chloride sponges, etc.) employed in many experimental 610 JONSSON AND OTHERS Ann. Surg. - November 1991 14 Collagen ,ug/cm #

13 -

12 # 1'

10 9.

# 7. # # 6-

5- # # 4-

* 2 # #~

1- I I~~~~~~ 0* iT 10 20 30 40 50 60

Post op hot %

FIG. 4. No correlation between collagen deposition on day 7 and hematocrit value was found. Data on day 5 were similar. studies, and was designed to be acceptable to human pa- recognized, provided that vascular supply to the arm is tients. Collagen deposition in these models correlates with intact, as it was in all our subjects. The PCO2, particularly the breaking (tensile) strength of healing wounds.26 The PSCO2 max, reflects the rate of perfusion of the wound ePTFE model has been used successfully to detect im- tissue, as noted by Gottrup et al.23 This relationship is paired collagen deposition in smokers and patients suf- made numerically more evident by the "perfusion score." fering from uremia and acute starvation, groups notable The current results from the combination of these for their high rates of wound complications.29-3' Tensile techniques agree with those obtained in animals by other strength of primarily closed wounds and collagen depo- investigators and extend to surgical patients the evidence sition in several models has been significantly elevated or that collagen deposition in healing wounds is clearly re- depressed in physiologically normal animals by changing lated to tissue Po2 but is independent ofthe hemoglobin only the oxygen tension of the breathing mixture. 1-3,5,6 content of blood over a wide range. Initially this circum- The silastic tonometer method of measuring subcuta- stance seems contradictory to established views that em- neous tissue oxygen tension has been used extensively in phasize the importance of hemoglobin in oxygen trans- patients and animals. 19,20,23,25,32,33 Insertion of this tube port, and deemphasize the importance ofarterial oxygen creates a small test wound that, unlike the ePTFE tube, tension. There would be no contradiction, even theoret- offers no unperfused space for inflammatory cells to ac- ically, however, if(1) oxygen consumption in the collagen- cumulate. The P,CO2 integrates many focal oxygen ten- producing tissue were low, and (2) ifthe rate of collagen sions, which range from below that of venous blood to synthesis were to depend on the ofoxygen almost as high as arterial P02 into a single mean value within the healing area. Both conditions appear to exist. that is generally 10 to 20 mm Hg above that measured The first condition, that wounds must consume rela- by identical technology in surgical (scalpel) wounds.34 The tively little oxygen, has been proved previously. As noted upper arm site was chosen for accessibility. No differences above the normal extraction of oxygen in these wound in healing between upper arm and abdomen or chest are models is approximately 0.7 volumes of oxygen per 100 Vol. 214 - No. 5 TISSUE OXYGENATION, ANEMIA, PERFUSION, AND WOUND HEALING 611 mL perfusing blood, an extraction ratio of only 3% in lower mean wound P02 is to increase the number ofanoxic normal volunteers.23 Even during air breathing, very little areas. In any case, it is difficult to escape the conclusion hemoglobin must give up its oxygen to supply such a small that local tissue oxygen tension influences collagen syn- amount, and even less is required when Pao2 rises above thesis and deposition in wounds in the normal range of 100 mm Hg. physiologic circumstances seen in surgical patients. The second condition, that the rate of collagen depo- Only small amounts ofunderhydroxylated collagen can sition is proportional to oxygen tension, is also consistent be exported from fibroblasts. Therefore the total collagen with established fact. Collagen synthesis is proportional deposited in the hypoxic patients can be only slightly un- to oxygen tension in cultured cells and tissues.3-6,35-38 derestimated. Furthermore underhydroxylated collagen Several potential mechanisms for this effect are found in is unlikely to contribute to wound strength. the details ofcollagen biosynthesis and post-translational Wound healing, collagen synthesis, deposition, and modification. In these processes collagen is modified by cross-linking ofcollagen are complex processes and many four enzymes that bind molecular oxygen and insert an other steps in them may be influenced by oxygen tension oxygen atom in appropriately positioned proline or lysine and blood perfusion. For instance the lysyl hydroxylase moieties. They are prolyl 4-hydroxylase, prolyl 3-hydrox- and lysyl oxidase reactions mentioned above also are P02 ylase, lysyl hydroxylase, and lysyl oxidase. dependent in the 0- to approximately 250-mm Hg range, The hydroxylation of proline by prolyl 4-hydroxylase but the significance of hypoxia with regard to their func- appears particularly pertinent. Its activity usually corre- tions is not known. Wound angiogenesis is increased by lates with the rate of collagen synthesis.39"' This enzyme increasing Pao2, " and this could indirectly affect collagen hydroxylates proline residues as the growing procollagen deposition in this model system. Unfortunately no meth- chains enter the endoplasmic reticulum. Molec- ods for measuring angiogenesis in human subjects are ular oxygen, oxoglutarate, Fe2+, and ascorbate are re- available. quired. When oxygen tension is lowered sufficiently, syn- These data apply to the long-debated question of thesis of collagen pro-alpha chains continues unabated whether anemia interferes with wound healing. In general while hydroxylation lags. The underhydroxylated collagen the effects ofanemia are mitigated by increased perfusion, pro-alpha chains that result from this circumstance fail which in turn is largely a result ofincreased to form a collagen triple helix that is stable at 37 C. There- and local blood flow due to decreased blood viscosity and fore they cannot be normally exported, and are eventually peripheral resistance. Because wounds consume little ox- excreted as nonfunctional .39 Fibroblasts have no ygen, P02 can be maintained by rapid perfusion with ane- means to compensate for a substrate deficiency in this mic at high P02 despite its low oxygen con- reaction. For instance without ascorbate, which serves as tent. Clearly, however, if perfusion cannot be enhanced, the oxygen radical donor in this reaction, collagen hy- wound healing in anemic patients will be exceptionally droxylation and subsequent collagen deposition are se- vulnerable. For instance wound healing must necessarily verely impaired. Because both ascorbate and oxygen are suffer if anemia leads to unmet cardiac oxygen needs. consumed, the effects of hypoxia and ascorbic acid defi- One of these patients (patient 25), who has sickle-cell ciency on collagen synthesis are theoretically identical.' anemia, maintained a normal PscO2 at a hematocrit of 15 The oxygen tension corresponding to the half-maximal to 20 but not below 15 on the first postoperative day when rate (Km) of the prolyl 4-hydroxylase reaction has been her PCO2 rose with transfusion from a hematocrit of 14% estimated by three sets of investigators at approximately to 18%. Her heart was normal, and despite her average 20, 25, and 100 mm Hg. 0 "2 Michaelis-Menten kinetics hematocrit of roughly 20%, her collagen deposition was dictate that ifall other substrates and cofactors are present average. Thus the critical range in which anemia influ- in adequate quantities, the rate at which collagen is hy- ences repair in physiologically normal surgical patients droxylated will vary in response to changes in P02 in the appears to be approximately 15, as Zederfeldt predicted range from 0 to approximately 10 times the in 1957 from experiments in animals.14 This critical range ofoxygen that corresponds to the Km. The V max ofthis is higher ifcardiac output is limited. In general moderate enzyme occurs therefore, at or above 200 mm Hg. Sub- anemia seems unlikely to affect repair in physiologically strate concentration effects the rate of product most pro- normal patients. foundly in the lower part of the concentration range. In Rapid perfusion can ensure only that wound-tissue P02 this case about 90% of the effect of oxygen is exerted in approaches Pao2. Desaturating , there- the range of0 to 90 mm Hg or more. Extracellular tissue fore, has its own effects on repair. Part of the wide vari- oxygen tensions in healing wounds have been measured ability oftissue P02 in these patients was due to depressed and normally lie in the range of 0 to 60 mm Hg.43 Focal Pao2 resulting from depressed pulmonary function (see areas of near-zero oxygen tensions have been found in Table 1). There were relatively few patients with serious experimental wounds, and it is reasonable to infer that to respiratory disease in this series, and they received vig- 612 JONSSON AND OTHERS Ann. Surg. November 1991 orous respiratory therapy. One (patient 32) was morbidly 2. Shandall A, Lowndes R, Young HL. Colonic anastomotic healing and oxygen tension. Br J Surg 1985; 7:606-609. obese. His Pao2 and Ps,O2 were kept high by a respirator 3. Niinikoski J. Effect of oxygen supply on wound healing and for- and endotracheal tube, and he deposited a relatively high mation of experimental granulation tissue. Acta Physiol Scand amount of collagen. 1969; 334(suppl): 1. 4. Hunt TK, Pai MP. The effect of varying ambient oxygen tensions The analysis ofvariables suggests that changes in arterial on wound and collagen synthesis. Surg Gynecol Ob- and tissue P02 accounted for approximately one third to stet 1972; 135:561-567. one halfofthe observed variability in collagen deposition. 5. Niinikoski J, Penttinen R, Kulonen E. Effect of oxygen supply on the tensile strength of healing wound and of granulation tissue. Our clinical impression is that another significant part of Acta Physiol Scand 1966; 277(suppl): 146. the variation in tissue Po2 in these patients was due to 6. Niinikoski J. Oxygen and wound healing. Clin Plast Surg 1977; 4: vasoconstriction. To minimize vasoconstriction we at- 361-374. 7. Sandblom P. The tensile strength ofhealing wounds. Systemic factors, tempted to optimize blood volume, but no attempt was anemia and dehydration. Acta Chir Scand 1944; 89(suppl): 1- made to control pain, fear, and cold, the other main stim- 108. ulants of peripheral vasoconstriction. 8. Guiney EJ, Morris PJ, Donaldson GA. Wound dehiscence. A con- tinuing problem in abdominal surgery. Arch Surg 1966; 92:47- The remaining variability may relate to measurement 51. errors, the limited time ofobservation (1-2 hours per day), 9. Bains JW, Crawford DT, Ketcham AS. Effect ofchronic anemia on or unmeasured variables. Goodson et al.,30 and also Hay- wound tensile strength: correlation with blood volume, total volume and proteins. Ann Surg 1966; 164:243-246. dock and Hill,3' have recently used the ePTFE tube 10. Polk HC Jr. Principles of preoperative preparation of the surgical method in surgical patients to relate acute preoperative patient. In Sabiston DC, ed. Textbook of Surgery, Vol 1. Phila- starvation to diminished collagen deposition. Two ofthese delphia: WB Saunders, 1986, p 90. patients 1 and were 11. Madden JW, Arem AJ. Wound healing: biologic and clinical features. (patients 7) unable to eat for several In Sabiston DC, ed. Textbook of Surgery, Vol 1. Philadelphia, days before operation, and they deposited relatively little WB Saunders, 1986, p 207. collagen. Albumin values did not correlate with collagen 12. Besser EL, Ehrenhaft JL. The relationship ofacute anemia to wound but the was healing. Surgery 1943; 14:239-245. deposition, range (3.0-5.1 g/dL) small. There 13. Waterman DF, Birkhill FR, Pirania CL, Levenson SM. The healing were two wound infections (patients 1 and 17), and one ofwounds in the presence ofanemia. Surgery 1952; 31:821-826. ofthese wounds dehisced. Both patients had low perfusion 14. Zederfeldt B. Studies on wound healing and trauma. Acta Chir Scand score, and low max. 1957; 224(suppl): 1-85. PCO2 15. Sandberg N, Zederfeldt B. Influence ofacute hemorrhage on wound In summary the present data confirm in human wounds healing in the rabbit. Acta Chir Scand 1960; 118:367-371. the effect of blood perfusion and oxygen tension on col- 16. Trueblood HW, Nelsen TS, Oberhelman HA. The effect of acute anemia and deficiency on wound healing. Arch Surg 1969; lagen deposition that has been seen previously in animal 99:113-116. wounds. The most tissue-hypoxic patients (perfusion score 17. Fong TP, Ko ST, Streczyn M, Westerman MP. Chronic anemia, 0-1, PsCO2 max approximately 50) accumulated 2 to 3 yg wound healing and red cell 2,3-diphosphoglycerate. Surgery 1976; collagen per centimeter ofePTFE 79:218-223. tubing, whereas the best- 18. Jensen JA, Goodson WH III, Vasconez LO, Hunt TK. Wound heal- oxygenated (perfusion score 3, PscO2 max approximately ing in anemia. West J Med 1986; 144:465-467. 90) accumulated 7 to 8 ,ug, or three times more. This 19. Gottrup F, Firmin R, Chang N, et al. Continuous direct tissue oxygen same difference is also seen in experimental tension measurement by a new method using an implantable animals.3'4 Silastic tonometer and oxygen polarography. Am J Surg 1983; The data reinforce the time-honored observation that 146:399-403. cardiopulmonary function and local perfusion are vital 20. Chang N, Goodson WH III, Gottrup F, Hunt TK. Direct measure- to wound healing. Conversely, but ment of wound and tissue oxygen tension in postoperative pa- placing the role ofar- tients. Ann Surg 1983; 197:470-478. terial oxygen content into perspective, they imply that 21. Goodson WH III, Hunt TK. Development of a new miniature pharmacologic manipulations of vasomotor activity are method for the study ofwound healing in human subjects. J Surg of major significance to repair. Lastly measurement Res 1982; 33:394-401. of 22. Grant RA. Estimation ofhydroxyproline by the autoanalyser. J Clin oxygen tension in wounds seems to have the potential to Pathol 1964; 17:685. guide therapy that may reduce wound complications and 23. Gottrup F, Firmin R, Rabkin J, et al. Directly measured tissue oxygen morbidity rates. tension and arterial oxygen tension assess tissue perfusion. Crit Care Med 1987; 15:1030-1036. 24. Evans NTS, Naylor PFD. Steady status ofoxygen tension in human Acknowledgments dermis. Respir Physiol 1966; 2:46-60. The authors thank Robert A. Upton, M.D., for statistical 25. HopfHW, Jensen JA, Hunt TK. Calculation ofsubcutaneous tissue consultation; blood flow. Forum and Cherry Elliott and Pat Sibley for chart research and manuscript Surg 1989; 34:33-36. preparation. 26. Viljanto J. Biochemical basis of tensile strength in wound healing. Acta Chir Scand 1964; Suppl 333. 27. Madden JW, Peacock Jr EE. Studies on the ofcollagen during wound healing. I: rate of collagen synthesis and deposition in References cutaneous wounds of the rat. 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