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Structure and function of the intraneural microvessels as related to trauma, edema formation, and nerve function G Lundborg; The Journal of Bone & Joint Surgery

To facilitate quantitative measurement of a delayed hypersensitivity reaction, a tuberculin reaction was produced in the paws of sensitized guinea pigs and the resulting edema estimated by one of the usual techniques. The edema formation was shown to be an expression of the delayed hypersensitivity reaction. Optimal conditions for this reaction were assessed. This model may be used for testing the influence of drugs on delayed hypersensitivity reactions.

In the rat, intravenous injection of minute amounts (7.9 mg/kg) of dextran induced edema formation of the same intensity as high doses (300–600 mg/kg). With the high doses, mast-cell disruption (histamine and serotonin release), vasodilatation, hypothermia, hypotension, hemoconcentration, and edema occurred. Since minute doses of dextran induced only vasodilatation and edema formation, this response is considered as the pure anaphylactoid reaction. The syndrome provoked by high doses is a consequence of conditions created by the physical presence of large quantities of dextran in the blood, rather than an integral part of the proper anaphylactoid sequence. Minute doses of dextran induced edema without mast-cell disruption, hypothermia, hypotension, or hemoconcentration, thus showing that the dextran response in the rat is mediated by factors other than histamine and serotonin of mast-cell origin.

The application of cold water to allay pain and reduce edema in burned skin is known to be effective. Evidence suggests that the immediate application of cold water to a burned area reduces spreading of injury and subsequent necrosis. Several mechanisms have been suggested as the primary reason for the inflammatory response that appears after thermal injury, one of these being a damaged circulation. The purpose of this study was to see if cold water protected the circulation and if it contributed in this way to reducing the effects of the burn. Microscopic observations of blood vessels in the bat's wing were made following thermal injury produced by heating a 3-cm diameter for 30 sec at 55°. Comparisons were made of the vessels of animals subjected for 4 hr to cold water (18–20°) flowing over the burned area and untreated animals. Significant differences were found in edema formation and subsequent renewal of normal flow.

A method has been devised to measure the spread of vital dyes in the skin of mice. Spread is greatly influenced by physiological and pathological changes which add fluid to the tissue or abstract it. Spread is greater in the quiet, living ear than in the ear of an animal just killed. It is equally considerable in the frankly edematous ears of living and dead animals, and not greater in either case than in normal, quiet tissues. During the early stages of edema formation on the other hand, dye spread is notably rapid. It is still greater in the ears of normal animals actively moving about, and is greatest in tissues subjected to very gently intermittent changes in external pressure. The significance of these findings is discussed.

Summary(1) A pulsatile perfusion system is described in which temperature, blood flow and mean pressure are controlled, and in which red blood cell solutions may be satisfactorily perfused through isolated limbs and organs. (2) In hind limbs perfused with blood of low colloidal content, 5.5 to 9.4 vol. % oxygen content were adequate in maintaining capillary function since a minimal rate of edema formation was observed which did not vary appreciably with flow. (3) Hind limbs perfused with 0.88 to 2.60 vol. % oxygen exhibited augmented edema formation which increased with increased flow. The critical hypoxemia level affecting capillary permeability is believed to lie between 2.6 and 5.5 vol. °/o oxygen content for the experimental conditions described.

The perfusate concentration of Ca++ has been assumed to be important for the permeability of the exchange vessels to proteins; low [Ca++] is said to result in edema development. The possible role of perfusate [Mg++] in this connection has previously not been considered. In the present work the correlation between the perfusate concentrations of Ca++ and Mg++ and edema development has been analyzed. In a perfused rabbit lung preparation edema developed at physiological intravascular pressures when the perfusate (plasma) [Ca++] was reduced to about 7. 10-5 mM and the [Mg++] to about 1. 10-3 mM by EDTA additions. Edema development was not seen at intravascular concentrations of Ca++ and Mg++ of about 4. 10-5 and 4. 10-1 mM, respectively. Such concentrations were achieved by addition of EGTA to the perfusate. Thus either the [Mg++] or the [Ca++] plus [Me++] in the perfusate must be the important parameter for the edema development. The changes in the capillary permeability induced by EDTA-additions were largely reversible by addition of Ca++. This effect of Ca++ had a latency period of less than one min.

Summary When hearts from rats were frozen with 15% dimethyl sulfoxide (DMSO) to −20°C and thawed, 80% resumed mechanical activity when the DMSO was washed out. Hearts treated similarly, except that the DMSO was 30%, failed to recover in all cases 8 except one. Hearts treated with 30% DMSO did not freeze. None of the hearts from animals pretreated for 4 days before the experiment with 2.0 mg per day of cortisone acetate and then cooled to −20°C with 30% DMSO resumed mechanical activity after warming. However, the cortisone did reduce edema formation in the hearts to 17% of that formed in hearts from untreated rats. The results demonstrate that 30% DMSO is toxic in rat heart preparations, in contrast to previous reports of the lack of toxicity of similar concentrations in other tissues.

Summary A standard procedure is presented to produce maximal edema in rats in 15±4 minutes by intravenous injection of a standard dose of dextran. A simple method is shown for obtaining the standard dose, which varies from 0.7 to 0.9 mg/100g. This constant inflammatory reaction is characteristically influenced by antihistamines and neuroleptics, delaying or inhibiting edema formation. The minimum dose (μg/100 g) of the drugs that inhibit edema is used as an index value to express efficacy. Advantages of this method lie in its rapidity, the small number of animals needed, the standardized edema formation with minute amounts of dextran, and also the extremely small amounts of test drugs needed for performing the quantitative bioassay.

The severity and time of edema formation is characteristically influenced by doses of dextran if injected intravenously into rats. The dose-response curve revealed that small doses of dextrans (0.1–0.8 mg/100 gm) provoke maximal edema formation within 10 minutes, while increasing doses produce less severe edema and delay in its appearance, until a critical dose is arrived at, which provokes no hyperemia and no edema at all. Further increase in dose provokes edema again. The critical dose is relatively sharp and characteristic for each type of dextrans. If antihistamines are injected simultaneously with the critical dose, edema appears with full intensity. Experiments suggest that dextrans contain two fractions with opposite effects, one which provokes the edema formation and another which inhibits the response.

Patients with metastatic carcinoid tumors may manifest a symptom complex referred to as the malignant carcinoid syndrome. These patients classically demonstrate cutaneous changes characterized by transient flushing (predominantly of the face) with areas of macular cyanosis within the flush. The central areas of the flush tend to fade, leaving erythema, blanching, and cyanosis. This phenomenon has been termed a red, white and blue response. Telangiectatic venules appear as the flushing becomes chronic. Evidence of edema formation has been noted only occasionally.

THE METHOD of Cartland and Kuisenga (1936) for the assay of adrenal cortical extract depends on the ability of the test material to maintain the life of adrenalectomizied rats; it requires the use of relatively large quantities of extract and a period of several weeks for each determination. A somewhat more rapid and sensitive method is that of Selye and Schenker (1938) which makes use of the changes in the acute response of adrenalectc miz;ed rats to temperature fluctuations. This procedure requires moderate quantities of the fluid to be tested and a period of 24 hours for its completion. In the course of perfusion studies on isolated frog's legs (Loewen-Tren- delenburg preparation) it was found that small concentrations of adrenal cortical extracts in the perfusate markedly affect the development of edema in the legs. The rate of the edema formation, measured by the successive changes in weight.

The synthesis and anti-inflammatory evaluation of a number of 2-(substituted amino)quinolizinium bromides, including some previously unreported analogs, are described. The more active compounds in inhibiting carrageenin-induced edema formation are those containing a p-alkoxyanilino group in the 2-position of the quinolizinium ring.

In a series of experiments performed on guinea pigs during the past two years, with the purpose of confirming the findings in experimental chronic nephritis which I have previously reported,1 some interesting observations in edema formation have been made. Twenty-one animals received subcutaneous injections of an aqueous solution of uranium nitrate, as follows: six received numerous injections of 0.5 m.grms. at frequent intervals; eight received several injections of 5 m.grms. at longer and irregular intervals; and seven received one or more injections of 10 to 15 m.grms. Four animals died within two weeks after the first injection, and can be excluded from the chronic nephritis series. The remaining seventeen survived for from three to twenty-three months after the first injection, and all showed kidney lesions of a chronic nature, similar to those which I have previously described.

The synthesis and anti-inflammatory evaluation of a number of 2-(substituted amino)quinolizinium bromides, including some previously unreported analogs, are described. The more active compounds in inhibiting carrageenin-induced edema formation are those containing a p-alkoxyanilino group in the 2-position of the quinolizinium ring.

The effect of CPPV on edema formation in lungs perfused at constant blood flow was studied in whole dogs and in isolated dog lungs. In intact animals, subjected to an increase in left atrial pressure relative to pleural pressure of 40 Torr, pulmonary shunts correlate inversely (r = -0.82) with the level of end-expiratory pressure (PEE). CPPV had no significant effect on total extravasation of liquid even though PEE higher than 20 Torr was effective in preventing liquid from accumulating in the airways. In isolated lobes, perfused at constant blood flow and at a venous pressure of zero, accumulation of liquid occurred when PEE was increased above 8–10 Torr. At comparable levels of pulmonary arterial pressure, an increase in PEE resulted in lesser accumulation of liquid than when pulmonary venous pressure was elevated. Morphometric measurements revealed no significant difference in the distribution of accumulated liquid within the lung parenchyma between lobes made edematous either by raising venous pressuure or by raising PEE. It would appear that CPPV, while beneficial in improving arterial oxygen tension in pulmonary edema, does not prevent extravasation of liquid in lungs perfused at constant blood flow. High levels of PEE appear to damage the lung by favoring accumulation of liquid in the extravascular spaces of the lung.

The term "congestive heart failure" identifies a clinical syndrome characterized by at least three components: First, there is venous congestion of the pulmonary or systemic circulations, usually both but sometimes separately; second, there is usually retention of salt and water by the kidneys, resulting in edema, and, finally, these processes are causally linked with a failure of cardiac function. Restoration of cardiac compensation by measures which act directly on the heart, such as digitalis, often results not merely in improved cardiac function, as evidenced by a rise in cardiac output and a shrinkage in heart size, but also in the relief of venous congestion and the renal excretion of edema fluid. Although edema formation is a secondary consequence of cardiac failure, it has become increasingly apparent that the relief of edema by measures which have no direct effect on the heart may also eventuate not merely in a striking improvement

Improvements in the technique for lung fixation by vascular perfusion have resulted in a better preservation of a duplex lining layer of alveoli. This method is exposed in detail; technical difficulties and the significance of artifacts are discussed. The structural features of this layer, as well as its derived composition, strongly support the notion that this lining layer represents the surfactant lining of pulmonary alveoli. The question whether this layer is artificially produced in the sense of edema formation is experimentally studied and denied. The possible relationship between morphological features and chemical composition is discussed. An attempt is made to explain the observed distribution of the layer.

It is apparent that the kidney is the organ ultimately responsible for the salt and water retention, hence the edema formation, in congestive heart failure, but why the kidney fails to excrete these substances normally in this disease state remains to be determined. Venous congestion, and renal venous congestion in particular, has been postulated as one of the factors playing a role in the decreased electrolyte and water excretions. Recent observations in animals and man lend support to this concept.

Arterial hypertension (HT) has been shown to promote the formation and spread of cerebral edema in animal models (1, 2, 3), but the effect of HT on intracranial pressures (ICP) in patients with acute brain injuries and impaired autoregulation has not been clearly established.

IN 1954 we corroborated in the laboratory1some advice that grandmothers had been providing their offspring for many generations—the benefits of the application of immediate cold water compresses as a treatment for small burns. Studies at that time suggested that immediate topical cooling of burned surfaces materially inhibited the expected increase in permeability of the capillaries in the burned area and retarded edema formation. Since that time several clinical reports have suggested that surface cooling exerts a favorable influence on the pathophysiology of the ordinary clinical burn. That much of the tissue damage following acute thermal injury occurs subsequent to the primary insult and is caused by factors other than temperature alterationper seseems well established.2,3The following study was undertaken as a preliminary investigation designed to further clarify the role of surface cooling in modifying the pathophysiology of the more extensive burn. Method Observations were

Summary and Conclusions1. Considering that the edema formation following experimental cold injury might be a factor contributing to tissue loss, the prevention of gangrene was attempted by controlling the edema by use of the enzyme hyaluronidase. 2. Tissues edematous after cold injury showed no further swelling and a significant decline in volume after local injection of the enzyme, presumably due to an increased absorption rate of the accumulated fluid. 3. The evacuation of edema did not influence the gangrene as it was observed to develop simultaneously and equally in treated and control extremities. It seems, therefore, that tissue necrosis is not primarily related to accumulation of edema in the region of injury.

Two patients with congestive cardiac failure were placed on a metabolic balance regimen and supplemental sodium chloride was administered. Weight changes in these patients could be closely correlated with the amount of sodium retention and appeared to be initially independent of brachial venous pressure thus supporting the concept that edema in congestive failure results from prinmary sodium retention rather than primary elevation in venous pressure.

A typical case of pulmonary edema associated with heroin intoxication is presented. The roentgenographic patterns and possible mechanisms of edema formation are discussed, and the importance of recognizing the triad of coma, miosis, and pulmonary edema is emphasized.

Notwithstanding frequent reports attesting to the value of homografting, there is still a reluctance to use the procedure freely and early enough to realize its fullest benefits. 11,14,18 This is partly due no doubt to the knowledge that the surface covering obtained is temporary, plus a belief that the procedure is too troublesome and elaborate to be practical. In our experience the ease of setting up on short notice a practical working scheme for homografting in surroundings that had never witnessed such a procedure before, the characteristically enthusiastic cooperation of the patient's friends and relatives who thereby gained a sense of participation in the task of getting the patient well and the immense sense of security given the surgeon by the possession of practically unlimited square inches of healthy skin in which to dress an extensively burned patient, make homografting seem to us a procedure of vast practical application and of particular common sense in the treatment of the acute extensive burn. There is no more desolate situation than to bring a major burn case successfully through the first forty-eight hours or so of burn shock, edema formation and resolution, then to be confronted with a vast denuded area demanding prompt skin coverage and to wonder from where the skin is going to come. Homografting, we think, supplies the answer. Despite firm conviction that early skin replacement is of paramount importance in the treatment of burns the tendency is strong and well nigh irresistible to wait weeks because of the poor condition of the patient, insufficient autogenous skin or a desire to be thrifty with what skin is left to the patient, and to use it only when a good take seems reasonably sure. All of these reasons for hesitancy spell delay, which may be fatal, and which can be circumvented by early recourse to homografting, a procedure which offers a generous supply of healthy skin at little or no physiologic expense to the patient and which can be undertaken to the great benefit of the sickest burn patient provided only that he be able to withstand the rigors of an extensive dressing. The authors would like to suggest that the nearest approximation to the ideal dressing for severely burned skin is a healthy split skin graft, autogenous or homologous. They would like, also, to suggest that the initial formal dressing of an extensively and deeply burned patient might well be a skin dressing of homografts procured from relatives or friends during the first two or three days of burn treatment and stored under sterile conditions of optimum refrigeration until needed, which is as soon as the patient's shock and edema fluctuations are controlled and corrected.

Backgrounds: For decades, fluid resuscitation in burn patients has been done as a routine process; most clinicians continue to adjust volume requirements using Parkland formula for the initial 24- hour period. In a variety of situations, there is increasing recognition of using significantly greater volumes than anticipated by the Parkland formula; clinicians tend to escalate volume requirements to drive the urine output to the higher end of any desired range. This excessive fluid could result in numerous edema-related complications, which currently coined as “fluid creep” phenomenon. Besides optimizing titration of fluid infusion rate, there have been studies of earlier and more liberal use of colloids, and even the use of hypertonic saline. The overall goal is to reduce the resuscitation volume requirements and subsequently, early edema formation.Conclusion: Current research in fluid resuscitation now concentrates on approaches to minimize fluid creep, including tighter control of fluid infusion rate. The single most important principle in using the Parkland formula, however, is that it should be used only as a guideline. The resuscitation rate and volume must be continually adjusted based on the response of the patient. Studies have been demonstrated to compare the use of crystalloids with early colloid in the first 24 hours post burn. At present, there are still wide variations in the timing of colloid resuscitation. However, use of 5% albumin in the second 24 hours seems to be an acceptable alternative.

The immunohistological method using the fluorescein antibody technique (direct method) was demonstrated to be proper for detecting the edema fluid in the brain. Serum leakage was observed mainly in the cerebral white matter in the renal hypertensive rat. Although the pathogenesis of the edema formation could not be clarified, the nature of edema fluid and the extent and location of fluid deposition in the brain can be detected. Advanced study can be expected with this method.

Local edema forniation caused by subcutaneous injection of 5-hydroxytryptamine (5-HT) was studied in unanesthetized, anesthetized normothermic and hypothermic mice. The edema was estimated quantitatively by a method involving the assay of extravasated trypan blue. Pento-barbital was used for anesthesia. The hypothermic mice were kept at a rectal temperature of 21–22 C. In unanesthetized and anesthetized normothermic mice the edema formation increased with increasing doses of 5-HT. At normal temperature light anesthesia greatly reduced the edema caused by 100 μg/ml 5-HT, but did not modify the edema caused by 10 or 1 μg/ml 5-HT. A lowering of the body temperature led to reduced edema formation, and the edema caused by 100 μg/ml 5-HT was relatively more reduced than that caused by 10 μg/ml 5-HT. The reduced edema formation under anesthesia and hypothermia might in part he due to increased constriction of the local arteries and arterioles under these conditions.

Plasma ADH levels in patients with chronic congestive heart failure were determined. In about half cases with moderate to severe right heart failure, ADH increased and it normalized after the cardiac function had improved. There were some cases where ADH increased in response to decreased circulating blood volume. In chronic congestive heart failure, ADH seems to play a role in edema formation together with aldosterone or change in the renal circulatlon.

IT IS NOW well established that the tissue damage 2,7 and death rates 6 which follow experimental burns can be significantly lessened by the early application of surface cooling. This finding has important implications for first aid and for the management of mass casualty burns. One of the problems which must be resolved before maximum benefit from this technique can be realized relates to the temperature of the cooling solution which can be expected to give maximum benefit. In this study we have investigated the effects of varying the temperature of cold compresses applied to standardized experimental burns in an effort to establish those temperatures which provide optimum improvement in the course of the burn. Method Methods have been previously developed for evaluating the capillary permeability changes and edema formation which follow experimental burns of several types. 4,9 These techniques will not be reported in detail here, but generally involve