The effect of hyperbaric oxygen on irradiated oral tissues: Transmucosal oxygen tension measurements

J Oral Maxillofac Surg 55:i 103-l 107, 1997

The Effect of Hyperbaric Oxygen on lrradia ted Oral Tissues: Transmucosal Oxygen Tension Measurements JENS J. THORN, DDS, PHD,* FINN KALLEHAVE, MD,t PETER WESTERGAARD,$ ERIK HJORTING HANSEN, DDS, DDSc@ AND FINN GOTTRUP, MD, DMSCI@ Purpose: This study measured the effect of hyperbaric oxygen (HBO) treatment on transmucosal oxygen tension in irradiated human oral mucosa. Patients and Methods: Ten patients received 30 dives of HBO as part of their treatment for mandibular osteoradionecrosis. A noninvasive, nonheated oxygen electrode was used to measure the tissue surface transmucosal oxygen tension directly on the attached gingiva. Measurements were done before, during, and after HBO treatment. The normal level of gingival surface transmucosal oxygen tension was measured in five healthy volunteers. Results: During HBO treatment, the transmucosal oxygen tension increased significantly after five dives of HBO (P < .05). After 30 dives, the increases were from a mean of 50% to a mean of 86% of the transmucosal oxygen tension of normal healthy gingiva. Conclusion: An increase in the transmucosal oxygen tension is based on neo-angiogenesis. Patients with subischemic tissues, such as the study population with postirradiation mucosal and osseous necrosis, therefore may benefit from treatment with HBO.

Osteoradionecrosis is an ischemic necrosis of bone caused by high-dose radiation therapy.“’ The mandible is the most commonly affected site in the head and neck region, and the clinical diagnosis is based on loss of soft tissue integrity and subsequent exposure of bone.3z4 Irradiated tissues are compromised by reduced vascularity and are thus hypoxic. Reduced cell number and metabolism add to the increased likelihood of spontaneous tissue breakdown and reduced capacity for wound healing.5*6

Hyperbaric oxygen (HBO) is used worldwide as an adjunct in the treatment of osteoradionecrosis of the mandible.7 Tt is believed to be the only way to increase vascularity in irradiated tissuesS8 However, this has been poorly documented in humans. Marx and colleagues’,’ did transcutaneous measurements in the central point of the radiation field as well as in a nonirradiated field before, during, and after HBO treatment. A steady increase in transcutaneous oxygen was seen in the irradiated but not in the control field. Granstriim et al” have recently reported a significant increase in transcutaneous oxygen levels in a group of patients treated with HBO for osteoradionecrosis when compared with a similar patient group not treated with HBO. Laser Doppler measurements were done subsequent to measurement of transcutaneous oxygen levels, and a doubling of the values was found in the HBOtreated group. The healing process is dependent on blood flow (perfusion) to provide tissue oxygenation. This can be measured using tissue oxygen tension techniques.“~‘* In osteoradionecrosis of the mandible, bone becomes exposed through the oral mucosa. However, transmucosal oxygen tension measurements have yet not been reported. In this study, the effect of HBO

* Associate Professor, Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen, Denmark. t Research associate, Copenhagen Wound Healing Center, Bispebjerg Hospital, Copenhagen, Denmark. $ Technician, Department of Anesthesiology, Rigshospitalet, Copenhagen. Denmark. 5 Head and Professor, Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen, Denmark. Ij Head and Professor, Copenhagen Wound Healing Center, Bispebjerg Hospital, Copenhagen, Denmark. Address correspondence and reprint requests to Dr Thorn: Department of Oral and Maxillofacial Surgery, Z 2002, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. 8 1997 American 0278-2391/97/551

Association of Oral and Maxillofacial O-001 0$3.00/O

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treatment on transmucosal oxygen tension in irradiated oral mucosa of 10 patients with mandibular osteoradionecrosis was evaluated. Patients

and Methods

Ten patients (four women, six men; mean age, 56 years; range, 46 to 72 years) developed mandibular osteoradionecrosis 2 to 4 years after termination of radiation therapy (64 to 66 Gy) for treatment of intraoral squamous cell carcinoma. Denuded bone was present 6 to 12 months before HBO treatment. The patients completed HBO treatment and transmucosal oxygen measurements from January 1994 to February 1996 at the University Hospital, Rigshospitalet, in Copenhagen. All patients were smokers except one. Five healthy controls (four women, one man; mean age, 51 years; range, 46 to 59 years) had transmucosal oxygen tension measurements done on healthy attached gingiva on two occasions but received no HBO treatment. The HBO protocol involved 90 minutes per dive at 2.4 ATA, one dive per day, 5 days per week. Patients received 20 dives preoperatively and 10 dives postoperatively. Three patients had superficial sequestrectomy of denuded bone done after 20 HBO dives. In two of them, the mucosa healed within 2 to 3 months. No healing took place in the third case, and this patient did not want any further surgical procedures. The rest of the patients had continuity resections and are all in the process of soft and hard tissue replacement and prosthetic rehabilitation. A noninvasive, nonheated modification of the Clark polarographic oxygen electrode (Cardiff electrode) was used to measure the tissue surface transmucosal oxygen tension directly on the gingival mucosa.13 The principle of the Clark electrode is that the reduction of oxygen (0,) molecules occurs on the platinum-cathode, and the current produced is directly proportional to the tissue oxygen tension. The electrode, with an external diameter of 12 mm, consisted of a single 0.9mm-diameter platinum cathode and a concentric silver anode, set in epoxy resin in a pencil-like design. The incorporated thermistor allows simultaneous measurement of the local tissue temperature. A 25-ym oxygenpermeable Teflon membrane, separated from the cathode by a thin film of 250 mg/mL KCl, was used to cover the electrode tip and was held in place by a rubber O-ring. The permeability of the Teflon membrane to oxygen increases with increasing temperature and necessitates taking into account the variations in the atmospheric pressure and the difference between the calibrational (ambient) and operational (gingival surface) temperature of the electrode. The latter was used in conjunction with the known temperature coef-

10 5-

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25 30 No. of HBO dives

FIGURE 1. Average transmucosal oxygen tensions of gingiva (and 95% confidence limits) in 10 patients with mandibular osteoradionecrosis during 30 hyperbaric oxygen dives. The increases were statistically significant after five dives of HBO.

ficient of the electrode to compensatefor the changing permeability. I4 The electrode has a linear current responseto changing oxygen tension, and the calibration was carried out in room air before use in each patient. The measurements were reproducible, showing variations of less than 23 mm Hg and a 90% responsetime of less than 60 seconds. The measurementswere taken in atmospheric air by application of the electrode directly on the gingival mucosa close to the necrotic ulcer before the HBO dive. A prerequisite for reproducible values was a moist but clean mucosa. The first measurement was done before HBO treatment. The next measurements were done after every five HBO dives the following day. Ninety-five percent confidence limits have been calculated for every fifth session(Fig 1). Statistical differences were determined by Student’s t-test for paired observations.

Results

The mean transmucosal oxygen tension of healthy attached gingiva in the five controls was 40.5 mm Hg, with a range of 39.8 to 41.2 mm Hg (Table 1). The mean transmucosal oxygen tension of irradiated attached gingiva before HBO treatment was 20.4 mm Hg, with a range of 16.6 to 23.2 mm Hg (Table 2). The transmucosal oxygen tensions gradually increased

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Table 1. Transmucosal Oxygen Tensions of Healthy Gingiva in Five Nonirradiated Controls Controls mmHg NOTE. sions.

1 39.8 Values

represent

2 40.9

3 40.3

the mean of measurements

4 41.2

5 40.2 on two occa-

during HBO treatment (Fig 1). After five dives, the transmucosal oxygen tension was significantly increased (P < .05) compared with pretreatment values. After 30 dives, the level of oxygen tension of the irradiated attached gingiva was a mean of 34.7 mm Hg, with a range of 27.8 to 40.0 mm Hg. Transmucosal oxygen tension in irradiated attached gingiva increased from a mean of 50% to a mean of 86% of the oxygen tension of healthy gingiva after treatment with HBO. The smallest increase was from 41% to 69%. This patient did not heal after sequestrectomy. The range of maximal increase was from 53% to 100%. Discussion

Although osteoradionecrosis is an accepted disease category for treatment with HBO as described by the Undersea and Hyperbaric Medical Society Committee on Hyperbaric Medicine,” there is still some doubt about the benefit and the effect of HBO treatment.16 Three randomized prospective human trials exist within the area of head and neck postradiation surgery, all done by Marx et a1.17-19 One study relates to the development of osteoradionecrosisin conjunction with tooth extraction in irradiated jawbone.17 In the second study, the successrate of bone grafts to irradiated tissueswas evaluated.‘* The third study addressedcomplications related to soft tissue flaps such as wound dehiscence, wound infection, and delayed healing.” All results were in favor of the HBO-treated groups. In a retrospective study, Granstrijm et all9 showed that the use of antibiotics and the time spend in the hospital are reduced considerably if HBO is provided. In a prospective study, the same group found significantly better healing in 15 patients treated with HBO compared with 12 patients treated without HB0.l’ Several other clinical studies report the use of HBO to be beneficial in the treatment of osteoradionecrosis,20-25 survival of maxillo-orbital titanium implants2’j and as a prophylaxis against development of osteoradionecrosis after tooth removal.27Others, however, have found no justification of HBO in relation to tooth extraction from irradiated jaws.28,29 It has been shown that a steep oxygen gradient is necessary for angiogenesis to occur during wound healing, that the capillary ingrowth decreaseswhen the gradient declines, and that the oxygen concentration

in inspired air affects the growth and density of the capillary network.30 In contrast to most other tissue damages,an irradiated field is characterized by a low oxygen gradient from the center of the irradiated site toward the nonirradiated tissue. The effect of HBO relies on the establishment of a steeper gradient in the irradiated tissues, supporting the endothelial cell response, and leading to neoangiogenesis3’ This is supported by studieson wounds in animal models with and without the use of HB0.32-34In an irradiated rabbit model, Marx et al* demonstrated a sevenfold increase in vascular density produced by HBO, when compared with both normobaric oxygen and air-breathing controls. In humans, Marx and Johnson’ have performed repeated biopsies before and after HBO treatment of irradiated soft tissue and found an increased number of apparently functional capillaries as well as an increase in fibroblastic cells. Remensnyder and Majno35 found that the oxygen tension of a tissue increases proportionally with the degree of neoangiogenesis.Therefore, neoangiogenesis in subischemic tissue can be studied by measuring the increase in tissue oxygen tension. In the transcutaneous measurement study by Marx and coworkers,‘Z9 an S-shaped curve was described, with a lag phase from HBO dives 1 to 6 when tissue oxygen levels remained unchanged at a level of 30% of the level in nonirradiated tissue. The rapid rise phase between dives 7 and 23 shows an increase of 82%. Thereafter, in the plateau phase,the measurementsleveled out and stayed at that level at least 4 years. These measurements are done on irradiated skin and formed the basis of the internationally used HBO protocol developed by Marx and coworkers for use on osteoradionecrosis of the mandible. Successful treatment of osteoradionecrosisoften relies on healing of the oral mucosa. However, no prior

Table 2. Transmucosal Oxygen Tensions of Attached Oral Mucosa in Ten Patients Irradiated (64-66 Gy) for Oral Cancer Before and During 30 Hyperbaric Oxygen Dives for 90 Minutes per Dive at 2.4 ATA Number Patients 1 2 3 4 5 6 I 8 9 10

of HBO

Dives

(mm Hg)

0

5

10

15

20

25

30

16.6 18.6 18.7 20.2 22.1 19.3 21.9 21.0 23.2 21.4

18.2 19.5 20.1 22.0 25.7 23.8 25.6 21.4 23.4 29.8

18.1 22.6 24.9 26.3 28.0 24.1 21.1 31.7 27.4 30.4

23.4 22.4 28.0 25.9 32.9 21.5 29.0 34.1 33.4 31.7

24.2 22.5 29.4 28.5 35.1 28.1 31.0 36.2 38.4 32.1

26.0 25.0 26.8 30.4 37.2 35.4 35.9 41.9 38.3 37.5

27.8 30.5 29.3 32.7 37.3 36.1 36.0 39.0 38.5 40.0

1106 studies on the reaction of irradiated oral mucosa are available. Flow evaluation has been done with laser Doppler on normal gingiva36 and oral mucosa,37 but evaluation of blood flow in oral mucosal tissues using tissue oxygen tension measurements have not been done previously. These measurements have been shown to be related to both tissue perfusion and oxygenation.‘1,‘2 In this study, measurements were done on attached keratinized oral mucosa. All controls had normal, healthy gingiva, and it appears from the readings in the five controls that the partial pressure of oxygen (PO,) in the surface of healthy attached oral mucosa is 40 to 41 mm Hg. The mean value of irradiated attached oral mucosa was 50% of normal mucosa, which was less than the decrease found in irradiated skin (30%) when compared with normal skin.‘Z9 Because the dose and the irradiation field were almost the same in the 10 patients, the observed range of initial values (41% to 57%) must have been attributable to a difference in sensitivity to irradiation and the time since termination of irradiation therapy. The one nonsmoker had an initial level of 56% of the normal values. In contrast to the initial low increase in oxygen tension found in the transcutaneous measurements of Marx and coworkers,“’ the values increased after the first session in this study (data not shown). This is probably because of a higher sensitivity of the probe used in this study and reflects an immediate response on the HBO therapy. From sessions 25 to 30, oxygen measurements decreased in one patient and leveled out in four patients, as in the terminal part of the S-shaped curve of Marx and coworkers.1Z9 In the final five patients, a further increase was found, and three of them reached almost normal levels. Future studies should show whether the oxygen levels obtained are stable, as in the skin, or whether there is a further increase, as indicated by the first few l-year readings (data not shown). The overall picture is a systematic increase in the pOZ values of the oral mucosa during the HBO treatment, which is statistically significant (Fig 1). The increase in tissue oxygen level is related to an increase in tissue perfusion and oxygenation,11X’2 which is based on neoangiogenesis in the irradiated tissue. For this reason, these data add to the evidence for the beneficial effect of HBO on angiogenesis in irradiated and subischemic tissue. From the irradiated rabbit model study of Marx et al,* it is known that neoangiogenesis of the overlying soft tissues is reflected in a similar, although lesser, development in the underlying bone. Acknowledgment The authors thank statistician Kaj Stoltze, DDS, for valuable advice and assistant professor Jorgen Kirkegaard, MD, and assistant

THE

professor work.

Erik

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Jansen, MD,

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