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Association of the Scientific Medical Societies in Germany (AWMF)

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Complete healing of chronic wounds of a lower leg with haemoglobin spray and regeneration of an accompanying severe dermatoliposclerosis with intermittent normobaric oxygen inhalation (INBOI): a case report

Case Report

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GMS Ger Med Sci 2011;9:Doc08

doi: 10.3205/000131, urn:nbn:de:0183-0001314

This is the original version of the article.
The translated version can be found at: http://www.egms.de/de/journals/gms/2011-9/000131.shtml

Received: July 30, 2010
Revised: February 20, 2011
Published: March 30, 2011

© 2011 Barnikol et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Abstract

A new healing procedure has been developed on the basis of the successful treatment of therapy-resistant hypoxic (and practically anoxic) leg ulcerations located within a heavy dermatoliposclerosis. The procedure involves an initial intra-ulceral application of haemoglobin followed by the intermittent administration of normobaric oxygen via inhalation. Haemoglobin is capable of externally supplying the granulating wound bed with oxygen at low partial pressure in a physiological manner, like a micro lung, so that oxidative stress can be avoided. A long-term daily administration of oxygen from within – including the peri-ulceral skin – is achieved by intermittent normobaric oxygen inhalation (INBOI) regularly throughout the day in the form of 1-hour sessions.

Using this combined healing treatment during haemoglobin applications the ulcerations healed within about 1 month, and subsequently with INBOI therapy within further approx. 4 months the peri-ulceral skin regenerated as far as the oxygenation status was concerned: The peri-ulceral transcutaneous oxygen partial pressure (tcPO2) of zero (measured during breathing of normal air) rose to a satisfactory value of approx. 35 mmHg. After 28 months of treatment, the completely hypoxic and degenerated skin on the leg had practically returned to normal with a PO2 of 45 mmHg. Furthermore, the skin dermatoliposclerosis regressed. The skin regeneration was long-lasting, which was probably related to cellular tissue regeneration with an increase in the capillary density, whereby it had to be maintained by regular oxygen inhalation (INBOI maintaining treatment). By unintended intra-individual therapy variations it is evidenced that local hypoxia was the reason for skin degeneration: 3 x 1 h oxygen inhalation were sufficient for the healing treatment; 2 x 1 h sufficed for maintenance, whereas 2 x 0.5 h did not.

The new procedure carries practically no risks, is simple, cheap and effective. Whereas the application of haemoglobin requires professional supervision, the oxygen inhalation can be carried out at home following initial guidance and monitoring by a physician. Using this novel method, the therapy-resistant ulceration could be closed within 5 months, during which daily outpatient care was only necessary for 1 month. The successful outcome of the treatment in terms of improvement of oxygen supply can monitored at any time using peri-ulceral tcPO2 measurements, whereby, due to the inhomogeneity of the values, measurements at a minimum of two locations at the wound edge are strongly recommended and more measurements at more skin locations would be preferable.

Besides its use in the healing of ulcers, the new procedure is also suitable for the prevention of ulceration development (prophylactic INBOI treatment) in skin rendered susceptible due to the presence of hypoxia. Here, peri-ulceral transcutaneous oxygen partial pressures of below 10 mmHg should be considered as being critical and are an indication for a prophylactic oxygen inhalation treatment. The new procedure may also be suitable even before the peri-ulceral oxygen partial pressure falls below 10 mmHg.

Four measures for rehabilitation, conservation, and prevention with regard to a healed chronic wound are proposed.

Keywords: chronic wounds, hypoxia of the skin as reason for chronic wounds, healing of chronic wounds, haemoglobin, tcPO2 as a measure of the tissue PO2, tissue PO2 as decisive quantity for the cellular oxygen supply, peri-ulceral oxygen partial pressure, tissue regeneration, intermittent normobaric oxygen inhalation (INBOI), dermatoliposclerosis, Hemo2spray®, 2 phases of skin regeneration, metabolic and cellular skin regeneration, arterial occlusion, low skin tcPO2 as indicator for chronic wounds, oxygen toxicity, microvascular (capillary) regeneration, controlled wound prophylaxis, controlled rehabilitation, maintaining treatment with oxygen, PO2 inhomogeneity, oxygen substitution


Introduction

Chronic wounds can occur which are refractory to treatment and in which the peri-ulceral transcutaneously measured oxygen pressures are practically zero (as is true in this case), whereas partial pressures of more than 40–50 mmHg can be found in healthy skin. We argue that such wounds can be treated only successfully by an oxygen substitution, because without sufficient oxygen no new tissue can be build up.

Previously, we have shown that it is possible to bring about the closure of chronic wounds showing oxygen deficiency by the use of externally (topically = intra-ulcerally) applied haemoglobin. In this setting, the healing was seen to take place more slowly, the lower the peri-ulceral transcutaneous oxygen partial pressure was [1].

A different approach therefore needs to be used if a practically anoxic ulceration is to be treated (as in this case): We have developed a concept in which a combination of a topical application of haemoglobin and intermittent inhalation of normobaric oxygen (INBOI) is used. Due to its damaging oxidative effects and the technical complexity, we decided that the use of hyperbaric oxygenation (HBO) was not an appropriate option in this setting.

The new therapy modality consisted of two parts:

(1) Initially, as described previously (see [1]), a haemoglobin solution was applied intra-ulcerally (daily) as a thin film in order to improve the external oxygen delivery and initiate wound healing.

(2) Thereafter or simultaneously, the internal oxygen delivery is increased by means of intermittent normobaric oxygen inhalation (INBOI) which is carried out for one hour several times per day over a prolonged period of time. An example of such a treatment is described below. By this procedure the oxygen partial pressure is demonstrably increased [2].

In principal, cleaned chronic wounds can be considered as being hypoxic cell cultures, which need to be additionally supplied with oxygen (both internally and externally) in a physiological manner if healing is to be achieved.


Previous history of the patient

General information

The patient was a 78-year-old male (born in 1927) who weighed 88 kg, was 174 cm tall and had suffered a fracture of the right lateral malleolus in 1982, which had been operatively treated. A resulting approx. 15 cm-long scar was evident above the ankle. In 1997, the patient suffered a left-side apoplexy with right-sided hemiparesis; in 1998 a left carotid stenosis was treated operatively, as was a right carotid stenosis in 2002. Over the course of time, the patient developed a type 2 diabetes mellitus with diabetic polyneuropathy and neuropathy (serum creatinine concentration: 2.8 mg/dL, clearance: 30 mL/dL). Blood pressure (RR) was noted as being 180/90. In 2004, stage IV peripheral arterial occlusive disease (PAOD) was diagnosed. Subsequent to occlusion of the popliteal and tibial arteries in the right leg, and with the existing ulcer above the lateral malleolus in the scar from the earlier operation, a percutaneous transluminal angioplasty (PTA) of both arteries was performed, but further surgical vessel restoration was deemed to be impossible. The patient received 2 x 20 drops of Novalgin® (metamizole sodium) for the severe and persistent pain.

Local events

An ulceration above the right lateral malleolus had been treated since 1998 in a dermatologist's practice. Previously (1997), erysipelas occurred during an eczematic reaction. Both the perfusion of the skin and the cutaneous oxygen partial pressure deteriorated steadily. Appropriate stage-related local treatment with rheological measures and gait training was carried out; at the beginning of 1999 a healing of the ulceration had been achieved. In November 2003 however, spontaneous ulcerations again became evident on the right lateral malleolus and by February 2004 the ulcerated areas has a length of 5 cm in total, with breadths and depths of 1 cm. An ozone/oxygen infusion therapy resulted in no improvement.


Findings and treatment

We saw the patient for the first time on 24.05.2004, when examination revealed a blood glucose content of 122 mg/dL, a blood pressure (RR) of 127/82, and a pulse rate of 58 min–1. Figure 1 [Fig. 1] shows the ulceration in question, located above the right lateral malleolus. The ulcerated area is in fact composed of two dehiscences which are only separated by a bridge of tissue. The distal ulceration showed pronounced undermining at the edges. Additionally, a distinct inflammatory dermatoliposclerosis with pronounced desquamation was present on the lower leg. The leg was oedematous and appeared as if it were mummified. The patient complained of severe and persistent pain (especially during the night) which occurred in particular when weight was put onto the leg, so that the patient could no longer sleep and at the same time was practically immobilized.

After an initial cleaning, we commenced daily treatment as described previously [1]: Coverings were carefully softened with highly concentrated urea preparations (30 to 40%) and thereafter the wound was cleaned by rinsing, and, if necessary, by mechanical debridement. Local disinfection and short-term oxygen delivery was achieved by placement of the foot in an oxygen chamber (plastic bag) for 30 minutes; this method of disinfection does not cause an allergic reaction [3]. The cleaned wound bed was treated daily with a 10% haemoglobin solution applied as a spray to produce a thin film and covered with an appropriate wound dressing (e.g., Chitoskin®, [1]). The peri-ulceral skin was protected from maceration by the application of Vaseline® or an ointment containing 10% urea. Prior to getting out of bed in the morning, the oedematous leg was bandaged with a compression dressing such that it was still comfortable for the patient.

So, the necessary additional standard measures we took at every wound treatment were: (1) cleaning the wound with highly concentrated chaotropic urea gel, (2) supplementary mechanical debridement, where required in local anaesthesia, (3) rinsing with isotonic solutions, (4) oxygen disinfection, (5) combined with haemoglobin solution moisture treatment (which is at the same time an amino acid substitution, as haemoglobin is hydrolised by the metalloproteases of the chronic wound), (6) application of hydroactive coverings to keep the hydrobalance, (7) protection of the wound edges, (8) adapted compression.

Whilst undergoing oxygen substitution (by intra-ulceral haemoglobin solution) combined with these treatments, the patient was free of pain during the night for the first time on 03.06.2004. On 09.06.2004, measurements performed during normal air breathing showed that the transcutaneous peri-ulceral oxygen partial pressure (see [1]) caudal to the lower dehiscence above the ankle (measurement point M3, see Figure 2 [Fig. 2]) was practically zero, as was the case with the dehiscence dorsal to the bridge of tissue (measurement point M2). The measurement of the tcPO2 values at the different locations could only be performed successively with one electrode.

In order to determine whether the supply of oxygen to the peri-ulceral skin was improved during oxygen inhalation in this patient, we carried out the following orienteering investigation: With the patient seated and inhaling oxygen via a mask covering the mouth and nose and the use of a puffer bag (oxygen flow was 15 L/min with gas overflow), the transcutaneous oxygen partial pressure at the M3 location (see Figure 2 [Fig. 2]) was seen to increase to 200 mmHg.

On 14.06.2004, the patient was completely free of pain, could walk without any problems and was taking walks outdoors. Figure 3 [Fig. 3] shows the ulceration on 16.06.2004. A newly developed wound bed can be seen at both of the open areas; the tissue bridge was reepithelialised. Daily wound treatment by a health professional was no longer necessary; instead, treatment could be carried out at home by the patient’s relatives. The topical application of haemoglobin was discontinued.

At this point in time, the peri-ulceral transcutaneous oxygen partial pressure as measured ventral to the tissue bridge (measurement location M1) rose to a normal value of 49 mmHg during inhalation of oxygen from an oxygen concentrator (5 L/min gas flow) using a mask with a puffer bag. After termination of the inhalation the quantity again fell to zero.

For a therapeutic, temporary improvement of the peri-ulceral oxygen supply using intermittant normobaric oxygen inhalation (INBOI), three hours inhalation per day were prescribed for the patient (one hour in the morning, at midday and in the evening, with the patient quiet and seated), who carried this out regularly at home.

On 20.10.2004 (after 5 months), the initially practically anoxic ulceration was almost closed (see Figure 4 [Fig. 4]) and wound care was no longer necessary. Nevertheless, bandaging of the leg was continued. At this point in time, the oxygen partial pressures measured during air breathing were 18 and 36 mmHg for the ventral and dorsal sides of the tissue bridge, respectively (see also Figure 5 [Fig. 5]).

Therapeutic oxygen inhalation was continued with the aim of complete healing. The peri-ulceral tissue underwent regeneration over the 5 months of oxygen inhalation therapy. Consequently, the decision was made to continue the oxygen inhalation in an effort to further increase the tcPO2 values.

Up until 04.05.2005 (after 11 months), the ventral value measured during air breathing (at measurement location M1) increased further to 39 mmHg, whereby the dorsal value (measurement location M2) was 31 mmHg (see also Figure 5 [Fig. 5]); at this point, the oxygen treatment was discontinued. Both wounds were completely closed, the surrounding skin did not appear to be irritated and felt soft again, i.e., the skin sclerosis was no longer evident.

On 14.10.2005 (after 17 months) the patient came back for a check-up. During air breathing, the transcutaneous oxygen partial pressure at the measurement locations M1 and M2 were now only 5 and 10 mmHg, respectively, i.e., the condition of the peri-ulceral tissue 6 months after discontinuation of the oxygen inhalation had deteriorated again (see Figure 5 [Fig. 5]). Figure 6 [Fig. 6] shows (see arrow), however, that no appreciable wound formation had occurred, although a small defect of the skin was visible and the peri-ulceral skin was distinctly reddened. The patient therefore resumed the regular intermittent oxygen inhalation – 3 hours per day – from 21.10.2005 onwards.

One month later, on 21.11.2005 (after 18 months), the transcutaneous oxygen partial pressure (tcPO2) was again measured at the measurement locations M1 and M2. During air breathing, the values obtained were 8 and 15 mmHg, i.e., the values had risen again by 3 and 5 mmHg, respectively (see Figure 5 [Fig. 5]). The skin defect had healed again and the redness was considerably reduced.

On 21.12.2005 (after 19 months), the transcutaneous oxygen partial pressure measurements at the M1 and M2 locations were repeated with values of 30 and 40 mmHg, respectively, being obtained. This meant that within two months, the values from 04.05.2005 had again been reached (see Figure 5 [Fig. 5]). The wound area can be seen in Figure 7 [Fig. 7] where the inflammation is seen to be considerably reduced.

On 20.01.2006 (after 20 months), the transcutaneous oxygen partial pressures were again measured and values of 43 and 33 mmHg obtained for the M1 and M2 measurement locations, respectively. The redness had regressed further. Compared to the measurements on 21.12.2005 only a slight increase in the partial pressure was evident (see Figure 5 [Fig. 5]).

Since previously, without treatment the partial pressure had decreased, a maintenance treatment was now considered necessary. Oxygen inhalation was prescribed, to be carried out two times per day (30 minutes each in the morning and evening).

At the check-up on 21.04.2006 (after 23 months), values of 21 and 9 mmHg were obtained for the M1 and M2 locations, respectively (see also Figure 5 [Fig. 5]), i.e., the maintenance treatment of 2 x ½ h oxygen inhalation proved not to be adequate.

This trend was confirmed in the further measurement taken after 25 months: The tcPO2 values for M1 and M2 were now only 2 and 10 mmHg, respectively, and had therefore, on average, declined further.

In an attempt to obtain a further regeneration, O2 inhalation was increased to 3 x 1 h per day. Within 1 month (i.e., after a complete total of 26 months), the M1 and M2 values in the healed wound rose to 43 and 47 mmHg, respectively.

After a further 2-month continuation of treatment, the values were 46 and 43 mmHg, i.e., no further increase was observed (see Figure 5 [Fig. 5]). In order to maintain this status, the O2 inhalation was set at 2 x 1 h.

After a further 6 months, the M1 and M2 skin locations exhibited tcPO2 values of 44 and 40 mmHg, respectively and had thus remained practically constant. It would therefore appear that 2 x 1 h O2 inhalation daily is adequate for maintenance of the tcPO2 values in the peri-ulceral skin, whereas treatment with 2 x ½ h is not.

The complete inhalation therapy in this patient continued for 34 months, i.e., almost 3 years. After 28 months, the oxygen status of the skin on the leg had returned to normal, with a value of 45 mmHg.


Epicrisis and discussion

The described individual case exemplarily shows how by the topical application of haemoglobin together with intermittent oxygen inhalation (INBOI) hypoxic, therapy-resistant wounds can be healed, and that after 1 year of treatment even a severe dermatoliposclerosis of the skin has disappeared. Both of these measures improve the supply of oxygen. This, in turn, facilitates wound closure by means of epithelialisation starting at the wound edge. In addition to the repair of the tissue defect, this treatment also resulted in a sustained rise in the oxygen partial pressure and thus to an improved oxygen supply to the skin area so that an enduring regeneration of the ulcer skin could be achieved. As is well known the most serious microvascular degenerations are found in dermatoliposclerosis and in chronic venous insufficiency, this is coiling or balling of the capillaries ([4], and accordingly [5]).

The evident linkage between oxygen supply (as assessed by tcPO2 measurements) and the state of the peri-ulceral skin (dermatoliposclerotic changes, existence of an ulcer) proves that in this case oxygen deficiency was the cause of the ulceration. That this was the case could be furthermore shown since the method used was able to reveal intra-individual variation (which is otherwise hardly ever possible in the medical field), albeit unintentionally, since after the first regeneration, the skin was seen to degenerate twice more, whereby on each occasion a further regeneration could be achieved by renewed application of this novel treatment.

As the decrease of the tcPO2 value precedes the wounding (see Figure 6 [Fig. 6]) this quantity is an appropriate early indicator of chronic wounding, and enables an effective and controlled prophylaxis.

Several reports on the successful treatment of chronic wounds using hyperbaric oxygen (HBO) support the notion that hypoxia is an important causal factor in this setting [6]. At the same time however, reports have been made in the literature claiming that an ulceration is never the result of oxygen deficiency [7]. These claims are, however, based on false assumptions [8].

To be able to plan an adequate individual and effective therapy it is essential that a chronic wound is characterised on the basis of its oxygen status. For this purpose, the only parameter that comes into question is the tissue oxygen partial pressure, since this represents the decisive driving force for the diffusion of oxygen to the cells mitochondria (where oxygen is primarily needed) and at the same time it is the decisive driving force for the signal of the electrode. Therefore, the tissue partial pressure is an analytical endpoint for the cellular oxygen supply and a measure of the tissue pressure is the transcutaneously assessed oxygen partial pressure of the skin (tcPO2).

Only the peri-ulceral measurement can be considered to provide a reliable and non-invasive assessment of the oxygen status in a chronic wound (since the ulceration itself is a local occurrence). However, measurement of the tcPO2 at two locations is not sufficient for “medium size” or bigger wounds (and even less so at only one location); much more information will be obtained by using simultaneous measurements at 4 peri-ulceral locations, or even at 6 locations, especially around large chronic wounds.

For the success and risk containment of intermittent O2 inhalation, it is important that this treatment is applied carefully and in a controlled manner. In order to ensure a maximum inspiratory O2 concentration, a mask similar to that shown in Figure 8 [Fig. 8] must be used. Tubes (so-called nasal cannulae) inserted into the nostrils to supplement the inhaled oxygen are not sufficient for INBOI. To prevent room air from being inhaled, the oxygen flow must be at least 7 L/min (i.e., the normal ventilation rate in humans), with 10 L/min being preferable since this rate would ensure an overflow. Appropriate O2 concentrators are commercially available. Nevertheless, momentary flow rates of up to 10 L/s can occur during normal quiet breathing. In order to buffer these high rates, it is necessary to use the shown bag.

The first O2 inhalation session should definitely be carried out under medical supervision, in case the patient’s breathing drive is oxygen-dependent. Even though this phenomenon is seldom, if it were to be present, it would lead to a breathing arrest.

By means of the attached O2 electrodes, it should be ensured that the inhaled oxygen really reaches the peri-ulceral skin [2], otherwise no success can be expected.

If the oxygen status of therapy resistant wounds is more frequently assessed in the future, it will be possible to see what proportion of such wounds are anoxic or hypoxic, whereby this is presumably very high. This is to be expected since both microvascular degeneration and oedematous tissue changes rapidly lead to cell hypoxia, since in both instances the intercapillary distance is increased and the already critical diffusion conditions for oxygen deteriorate further.

The healing of the ulcer and the regeneration of the surrounding skin are rather remarkable, when the reaction of normal tissue is considered, since intact tissue capable of regulation (with the exception of the lungs) reacts to an excess supply of oxygen with a blood vessel constriction. A peri-ulceral, extremely hypoxic tissue area showing vessel degeneration is, however, presumably in a functionally decompensated state, in which the above-mentioned physiological mechanisms for oxygen-regulation no longer operate since the controlling elements responsible for this regulation are unable to fulfil their task. The result of this situation is a favourable shift of the perfusion into the decompensated hypoxic tissue.

Pure or too highly concentrated oxygen is – when present permanently – oxidatively toxic for any type of tissue [1]. During hyperbaric oxygenation (HBO), the organism is confronted with an excess pressure of up to 2–2.5 bar, which in the case of pure oxygen results in a very unphysiological oxygen partial pressure of more than 2000 mmHg; this imparts to oxygen a very high oxidative potential, e.g., resulting in detrimental lipid oxidation. The lungs are particularly affected and – due to oedema development and a resulting disturbance of the pulmonary diffusion – a paradoxical systemic oxygen deficiency can develop.

For this reason, our treatment (topically applied haemoglobin and intermitted normobaric oxygen inhalation, INBOI) involves the use of oxygen in a much less unphysiological manner: Haemoglobin releases its bound oxygen locally to the cells under the usual relatively low partial pressures [1] and regenerates the wound bed at the cellular level. An increase in the oxygen partial pressure to approximately 50–60 mmHg is sufficient for wound healing.

Due to the known toxicity of oxygen, a significant extension of the duration of normobaric oxygen inhalation is not to be advised, especially in the case of elderly persons, who are already often weakened as far as pulmonary function is concerned; nevertheless, maximum treatments of 3 to 4 hours per day did not result in lung damage; here, the intermittent form of treatment represents a safety measure as opposed to an equivalent period of continuous inhalation in one session.

In this context, the findings reported by Alleva et al. [9] are of considerable interest. The authors found that wound healing during hyperbaric therapy (HBO) could be further improved when a course of antioxidative medication was given at the same time. This indicates that a hyperbaric therapy, besides having a healing effect, can at the same time cause (oxidative) damage. It would therefore seem advisable to initially try and heal therapy-resistant wounds with an isobaric, physiological, oxygen therapy, before an attempt is made with a more complicated, more expensive and higher risk hyperbaric oxygenation treatment. It may also be appropriate to use an anti-oxidative medication as a preventive measure even during normobaric O2 inhalation.

Strictly speaking, due to the risk of pulmonary oedema, the maximum reasonable daily inhalation time for a long-term treatment should be limited to 3–4 hours. In critical cases, however, inhalation may also be performed during sleep, but even here, the O2 inhalation must remain intermittent and should never exceed 1 hour.

The primary aim of intermittent normobaric O2 inhalation is to subject the hypoxic tissue to “healing periods” with sufficient oxygen supply under conditions as close to the physiological situation as possible, in this case for up to 3 individual hours per day. It is astonishing that under such treatment, the tissue appears to improve its oxygen supply. If this were not the case, the rise in the peri-ulceral oxygen partial pressure (during air breathing) from 0 to approx. 30 mmHg and finally to above 40 mmHg as found in this case would be incomprehensible.

During long-term, normobaric treatment it therefore seems that the tissue receives assistance which allows it to further help itself, so that even when treatment is not actually being applied, the oxygen status of the ulcer tissue gradually improves, which in turn accelerates the healing process; this also explains the effectiveness of the relatively short treatment times of only a few hours per day. Presumably first a functional regeneration is taking place (metabolic regeneration: 1st phase of skin regeneration, see below).

Besides the 3 “fast” augmentations (over months), the course of the tcPO2 values additionally shows (as a 2nd phase of skin regeneration) a slower increase over 28 months from approx. 35 to 45 mmHg (see the blue dotted line in Figure 9 [Fig. 9] demonstrating this), i.e., ¾ of the total effect occurs “quickly” and ¼ slowly.

Such a slow regeneration also explains why the treatment-induced increase in tcPO2 (on a total of three occasions, see Figure 5 [Fig. 5]) takes place with increasing rapidity.

A very similar behaviour is seen when external oxygen supply is increased to improve skin with cellulite (3 treatments per week) and the elasticity is measured cutometrically: A “fast” relative increase in the elasticity of 40% (⅔) was seen after 4 weeks, with a slower increase of 20% (⅓) requiring a further 6 months [8]. It is generally known that firstly, collagen makes up 80% of the skin mass and therefore determines skin elasticity and secondly, that collagen synthesis is strongly oxygen-dependent [10].

In both of the mentioned cases, the skin regeneration was seen to occur in two phases: a “fast” and a slow phase, whereby the slow phase in the case of dermatoliposclerosis lasted 28 months. We interpret the fast regeneration as being metabolic-functional and the slower as being a cellular-structural e.g., growth of arterioles and capillaries (a proof for this would be an improvement of the state of capillaries regarding structure and density). The obvious difference is that in the case of dermatoliposclerosis skin regeneration lasts years, whereas in the case of cellulite this time takes only weeks.

In our case however, the tcPO2 increases were not self-perpetuating; the peri-ulceral oxygen partial pressure during air breathing was repeatedly seen to decrease to between 5 and 10 mmHg, while at the same time initial tissue defects again became apparent (see Figure 6 [Fig. 6]), suggesting that a (permanent) healing was not occurring, but rather a (at least predominant) functional compensation with healing of the ulcer. That the microvascular regeneration does not endure in the long-term can be explained – in this case of stage IV peripheral arterial occlusive disease – by the fact that the macrovascular oxygen supply is not sufficient to maintain the therapeutically achieved microvascular regeneration permanently. This is due to the fact that the macrovascular circumstances are presumably not improved by oxygen inhalation.

Since the therapy effects are not self-perpetuating, our patient required a maintenance treatment with oxygen capable of ensuring that the oxygen supply to the peri-ulceral tissue did not deteriorate again. Most probably a graded medium (maintenance) therapy would be appropriate, considering the fact that without treatment the tissue condition worsened, whereas with 3 hours of treatment per day it improved. At the moment it is not possible to say exactly how many hours are necessary for a maintenance therapy, though it is surely less than that used for the healing and prophylactic treatments. A maintenance treatment probably needs to be individually “titrated” using transcutaneous measurement of the oxygen partial pressure. In our case, a maintenance therapy of 2 x ½ h (in the morning and evening) proved not to be sufficient, whereas a treatment of 2 x 1 h was. Even a maintenance therapy should be controlled from time to time (approx. every 2 months).

Certainly, also chronic wounds exhibiting oxygen tensions not smaller than 5 mmHg will heal faster, if the new method is used for support.

It is evident from Figure 5 [Fig. 5] that from month 19 to 20 and from month 26 to 28 no further increase in the peri-ulceral partial pressure was achieved. Apparently, a further rise in the peri-ulceral partial pressure once treatment was discontinued was not possible in the given clinical situation. Only slow cellular regeneration processes, i.e., a microvascular tissue regeneration, have the ability to achieve this, as the increase of approx. 7 mmHg from month 19 to 28 shows (see Figure 5 [Fig. 5])

The successful re-regeneration seen in this case study also suggests that prophylactic oxygen inhalation could be appropriate as a therapy form. An indication for this would be hypoxic skin which is beginning to show signs of tissue degeneration, e.g. pigmentation and/or white atrophia. Apparently, the reduction in the peri-ulceral oxygen partial pressure precedes the formation of the ulcer (see Figure 6 [Fig. 6]), so that this can serve as an early warning and be the signal for such a preventative O2 inhalation.

So, in principle there are therefore 3 treatment types for oxygen inhalation with different initial situations or objectives: (1) the actual healing treatment to assist wound healing, (2) when necessary, a maintenance treatment with reduced inhalation duration following healing of the ulcer, and (3) a prophylactic (preventative) therapy for different grades of hypoxia and the threat of tissue degradation, aimed at preventing ulceration. All of these treatments can be carried out (inexpensively) at home.

Maybe, INBOI is of special interest for homes for the aged, where preventive measures have to be taken against bedsore, which is caused by local tissue compression hypoxia. In aged skin geometrical conditions for oxygen diffusion already have changed to the worse due to distortion of capillaries, which are seen in capillary microscopy. But this has to be figured out clinically.

Bongiovanni et al. report that they successfully treated 231 patients with venous ulcers also using oxygen [11]. Alongside a consistent therapy, they exposed the leg bearing the chronic wound to 2.5–3.0 bar pure oxygen while at the same time, for 4 hours per day, the patient breathed pure oxygen via a mask. The leg was simultaneously positioned in a local oxygen positive pressure chamber, which is quite a complicated procedure. We consider a treatment of 4 h continuous systemic and local oxygen treatment with stoppage of the leg circulation, together with the subsequent reperfusion damage, to be a far too great oxidative burden for the organism.

At the initial examination we saw – in addition to a pronounced dermatoliposclerosis – that the complete critical skin area showed a distinct redness (see Figure 1 [Fig. 1]). The physicians who had previously treated the patient had classified this as an eczematous erysipelas. By the time the wound was completely healed, the redness was no longer evident, but reappeared with the deterioration of the oxygen situation in the intact skin (see Figure 6 [Fig. 6]). The redness subsided again after oxygen inhalation concomitant with an improvement in the oxygen partial pressure (see Figure 7 [Fig. 7]). It seems appropriate to assume that this was a hypoxia-induced, non-bacterial inflammation. If this is indeed the case, it is further evidence for an anti-inflammatory effect of oxygen, as has previously been described (see [1]).

Only a single case has been presented here, nevertheless, as discussed here, the observation of the course of events and the unintended therapy variations provide a considerable degree of reliability regarding the underlying pathophysiological mechanisms. The new method needs to be tested and evaluated in further clinical cases and case series. Nevertheless, when a serious, problematic case in the form of a therapy-resistant, hypoxic (practically anoxic) ulceration presents, therapists can apply this treatment since, in the hands of professionals, it is practically free of risk. Besides, after our application of oxygen inhalation, we found speculations from M. von Ardenne concerning wound healing with oxygen inhalation treatment [12].

Whenever it is possible to successfully close a chronic therapy-resistant wound with the new treatment, measures against a recurrence – depending on the cause – should already be taken during the treatment. Four steps (which may be combined) should be considered: (1) instructions to the patient concerning his/her own welfare (e.g., diet, weight reduction, exercise), (2) consistent compression (bandage, support stockings) – as far as it makes sense, (3) vascular surgical intervention, and (4) a lasting, intermittent oxygen inhalation therapy (INBOI), whereby, depending on the results in each individual case, this should commence with 2 x 1 h oxygen inhalation per day, accompanied by the assessment of the oxygen partial pressure.

It is possible that the described method using intermittent normobaric oxygen inhalation (INBOI) may also be suitable for a successful treatment of hypoxia in other (internal) organs such as the heart, brain or ear or in conditions such as hypoxic kidney or liver failure. Such treatments should obviously be attempted using a suitable control appropriate to the given case. At the moment there is no evidence to suggest that a metabolic and cellular regeneration is not possible in other tissues.


Notes

Competing interests

The authors declare that they have no competing interests.


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