HYPERBARIC OXYGEN THERAPY AND PIRACETAM
DECREASE THE EARLY EXTENSION OF DEEP PARTIAL THICKNESS BURNS

P.Germonpré, M.D.*, P.Reper, M.D.**, A.Vanderkelen, M.D.**
*Center for Hyperbaric Oxygen Therapy
**Burn Center, Military Hospital Queen Astrid
Brussels, Belgium

Abstract

During the first 24 hours, a progression of the burn wound in histological depth or extension is often noted. This can only partially be prevented by the routinely used protocols of fluid resuscitation and burn wound dressing. In a rat model of 5% TBSA burn, Hyperbaric Oxygen Therapy (HBOT) and Piracetam were evaluated for their ability to further prevent this early deepening of the burn wound. After infliction of the burn wound, the animals were treated with an accepted basic burn wound treatment consisting of mafenide 10% solution humid dressings. They were then randomized into three groups: a control group (n=10), receiving no other treatment, a HBOT group (n=17), receiving 60 minutes of HBOT (2 atmospheres absolute) twice daily, and a Piracetam group (n=19), receiving Piracetam (200mg/kg IM) twice daily. On the third day of treatment, the entire burn wound was excised and examined histologically. We found that both HBOT and piracetam had statistically significant effects on the preservation of skin appendages (p=0.003 and 0.007, respectively), epidermal basal membrane (p=0.001 and 0.002, respectively) and on the degree of subepidermal inflammation, as measured by leucocyte infiltration (p=0.001 and 0.038, respectively). The HBOT group showed furthermore significantly less leucocyte infiltration than the Piracetam group (p=0.001). We conclude that, although the clinical importance of the small effect on skin appendage and basal membrane preservation may be questionable, the effect on subepidermal leucocyte infiltration is striking and warrants further investigation to the anti-inflammatory effects of HBOT and possibly Piracetam.

Introduction

Since Jackson (1953) (1), it is generally accepted that a cutaneous burn wound consists of three distinct zones, each with its own histophysiological caracteristics: a central zone of coagulation necrosis, surrounded by a zone of established edema and capillary stasis, which is in turn surrounded by a zone of active edema formation. Another related concept, that of a progressive capillary stasis, reversible if dehydration of the burn wound is prevented, was described by Zawacki in 1974 (2). It is, however, a very common observation in serious burn patients, that areas that seemed to be "partial thickness" burns have to be regraded the next day as "full thickness", despite optimal fluid resuscitation and burn wound coverage (3). This progressive necrosis of tissue cells is closely linked to the degree of edema formation. Edema precedes capillary stasis, which in turn provokes capillary sludge by "rouleaux" formation of the red blood cells and finally capillary thrombosis. The end-point is tissular hypoxia, ischemia and cell death. Several therapeutic measures have been proposed to prevent this cascade. Some are widely accepted, such as early wound coverage and optimal osmotic vascular filling. Other drugs and physical measures have not gained wide acceptance.

We wanted to investigate if Hyperbaric Oxygen Therapy (HBOT) or Piracetam, associated to a classically accepted burn wound treatment, are able to limit the extent of this ongoing tissue damage during the early phase of burn injury.

HBOT is an effective means of augmenting the oxygen content of arterial blood. During HBOT administration, paO2 values as high as 1800 mmHg can be obtained, resulting in the physical dissolution of considerable quantities of oxygen in the plasma (Henry’s Law). This hyperoxia induces a generalized arteriolar vasoconstriction, without impairing the oxygen delivery to the tissues. Transcutaneous and intratissular measurements of pO2 in the limbs of patients undergoing HBOT, reveals that the peripheric oxygen delivery can be more than tenfold as high as in normobaric 100% oxygen breathing (4). Piracetam is a pharmacological substance, widely used in the treatment of cerebral vascular insufficiency, but also, because of its rheological properties, in the early phase after free tissue grafts with vascular micro-anastomosis, and in the treatment of frostbite.

Material and methods

The experimental model developed by Kaufman et al. (5), has been used. It has been shown to reproducibly create a partial thickness burn wound of approx. 5% TBSA, progressing to a full thickness wound if desiccation of the wound is not prevented. It also has a very low intrinsic mortality rate. A few adaptations have been apported, resulting in the following experimental protocol:

Experimental animal: Female Wistar rats of 200 grs (±20 grs) are used. The animals are housed in standard cages, submitted to a 12 hrs light/dark cycle and fed with standard rat chow and water ad libitum. 24 hrs before the test, the animals are shaved circumferentially on the abdomen and back, and carefully depilated with anti-allergic thioglycolate cream.

Burn wound: Three aluminium cylinders, of exact dimensions (diameter 3.76 cm, height 3.78 cm; total weight 500 grs) are placed in a hot water bath (75°C) for at least 1 hour before the beginning of the tests. The animal is anaesthetized with Hypnorm(R) (Fentanyl Citrate 0.315mg/ml + Fluanisole 10mg/ml) 0.15ml/100mg body weight I.M. This dosis provides for a good anaesthesia during approx. 3.5 hrs. The rat is then taken in the left hand, with the right flank exposed. One of the cylinders is taken out of the water bath, and is placed immediately on the exposed skin for 10 seconds. No supplemental pressure is applied. The application time is measured with a chronometre. However, neither extra pressure nor a prolongation of the application time would have had a significant influence on the thermal energy transfer to the skin (5). Surface temperature measurements are performed at the surface of the cylinder (Therm 2285-2, Enginel, Brussels), before and after each application, and show temperatures of 74°±1°C before, and 69°±2°C after the application. The three cylinders are used alternatively, so that each cylinder is allowed a rewarming time of about 10 minutes. In a series of preliminary experiments, biopsies have shown that this method results in a uniform deep partial thickness burn wound, progressing, over a 24-36 Hr period, to full-thickness even when humid dressings are applied.

Burn wound care and resuscitation: Immediately after burn injury, the wound is covered with a dry sterile gauze and the animal is left for four hours without any treatment. Then, two punch-biopsies (2mm²) are taken from standardized parts of the burn wound, and a wound dressing is applied, consisting of a sterile gauze, impregnated with 10% mafenide solution. The dressing is covered with an impermeable membrane (Opsite(R)), and with two layers of adhesive elastic circular bandage (Tensoplast(R)). No fluid resuscitation is given.

Ancillary Treatment: The burn wound dressing is changed daily, under light anesthesia (Hypnorm(R) 0.05ml/100g I.M.). The animals are randomized into three groups, by an independent person, not present at the time of burn wound infliction. The control group receives no ancillary treatment. The "Piracetam group" is given 200mg/kg Piracetam I.M. (UCB Pharma, Belgium), the first injection being given 4 hrs after the burn. The "HBOT" group is submitted to hyperbaric oxygen for 60 minutes, every 8 hours the first day, every 12 hours the following 2 days. The first treatment is given 4 hrs after the burn.

Hyperbaric Oxygen Therapy: HBOT is performed in a small experimental hyperbaric chamber of 60 litres. The animals are placed with their cage inside the chamber, which is preliminary flushed with 100% oxygen for 5 minutes. Then, over a 5 minutes time period, the chamber is pressurized with 100% oxygen to 2 atmospheres absolute (ATA). After a plateau phase of 1 hour at this pressure, ensuring a constant ventilation with 100% oxygen (to prevent CO2 build-up), the chamber is depressurized over a 5 minute period. This HBOT protocol is similar to the generally accepted protocols in the treatment of burns in the human patient.

Morphologic Assessment: Each animal is weighed daily, before treatment. The punch biopsies, taken on day one, are immediately fixed in Bouin's solution for one hour, then in a 15% formaldehyde solution. At the end of the study period, the animals are terminated by ether inhalation and the burn wound is excised entirely, to the fascia. A small (1cm²) flap of unburned skin is included in the excision at the proximal end of the wound, to serve as a intra-individual control. The excised wound is fixed in Bouin's solution for one hour, then in a 15% formaldehyde solution. After fixation, three histologic preparations are made. The first one is a horizontal cut through the middle of the entire specimen and the flap of unburned skin. The other two are horizontal cuts through each of the remaining parts.

Standard haematoxylin-eosin coloration is performed, and the specimens are assessed by an independent pathologist, experienced in the appreciation of burn wound specimens, in the following way: - punch biopsies: a global histologic appreciation is made, classifying the specimens in first, second or third degree burn, according to the standard histologic criteria of epidermal necrosis, subepidermal dehiscence and skin appendage necrosis. - excised burn wound: - reference skin flap: the number of skin appendages per microscopic field (100x) is counted and is considered an indicator of the general type of skin. - burn wound: four microscopic fields (100x) are analysed in the central horizontal preparation, and two more in the upper and lower part of the burn wound (six fields in total). In each microscopic field, the following parameters are evaluated: a- number of destroyed skin appendages, criteria for destruction being: presence of round or pyknotic cells, disappearance of hair follicle roots, abnormal coloration of the cytoplasm b- degree of destruction of the epidermal cover, with estimation (in n/4) of the integrity of the basal epidermal cell layer c- degree of inflammation: per microscopic field, attribution of a score: 0 (no dermal nor hypodermal inflammation), 1 (moderate inflammation, leucocyte presence concentrating around hair follicles), or 2 (severe inflammation, abundant leucocytes present in all skin layers).

Statistical Analysis: For each animal, a global score for all 6 microscopic fields is calculated for each of the three histologic parameters. The means per group are then calculated, and the groups are compared using a one-tailed Student's t-test, with the null hypothesis being the similarity of all groups. All statistical analyses are performed on an IBM PC, by means of SPSS-PC 4.0.

Results

50 rats have entered the study. Early mortality was 4/50 (8%). No exact cause of the deaths could be given; however, anafylaxis due to the Hypnorm(R) injection could not be excluded, since one of the animals died even before the epilation could be performed. The 46 remaining animals were randomized, after the burn wound, into three groups: Control group (n=10), Piracetam group (n=19) and HBOT group (n=17).

The evolution of body weight is given in Table 1. No statistical differences are observed between the 3 groups.

Analysis of the excised normal skin flaps does not show any significant difference between the three groups (Table 2)

All punch biopsies on day one have been classified as "superficial partial thickness wound", with edema formation, subepidermal dehiscence, preservation of appendages to the superficial third of the dermis.

Percentage of destroyed skin appendages on day 3: significantly less appendages are destroyed in both experimental groups (Table 3). The difference between the Piracetam group and the HBOT group (0.64 vs 0.61) does not attain statistical significance (p=0.17).

Destruction of epithelial basal layer: here again, significantly less destruction has taken place in both experimental groups (Table 4). Also, the difference between Piracetam (0.78) and HBOT (0.73) groups is significant (p=0.02).

Degree of dermal and subepidermal leucocyte infiltration (Table 5): here, the Piracetam (0.60) and HBOT (0.47) groups are significantly different from the Control group (p=0.038 and 0.001, respectively), but i also highly significant between the experimental groups themselves (p=0.001).

Discussion

a. Burn Depth

Depth and extension of the burn wound surface are two of the most important determinants of both mortality and morbidity of the burn injury. Although, in recent years, immediate mortality - due to "burn wound shock" - has decreased significantly, owing to the more efficiënt fluid resuscitation protocols and the more aggressive surgical approach (early tangential excision), a considerable portion of the burn-related deaths now occurs during the weeks after the insult. These deaths are mostly due to multi-organ failure, respiratory insufficiency and/or systemic infection (6). As for morbidity, the risk of delayed burn wound healing and hypertrophic scar formation is directly dependent of the depth of the burn wound and hence its chances of re-epithelialising spontaneously. The longer the duration of the healing process, the higher the risk of wound infection, further compromising proper burn wound healing (7, 8, 9).

Apart from the direct cellular death by heat-induced denaturation of proteins, a delayed and progressive necrosis is observed in the zones around the primary burn injury. A number of factors have been associated with this progression of cellular necrosis.

Zawacki (2) has described a progressive capillary stasis in second degree burn wounds, and was able to distinguish two phases:

• 0-4 hours: period of edema formation, progressive capillary stasis
• 4-24 hours: stabilisation of edema and capillary stasis.

By preventing dessiccation of the burn wound in this model, a reversal of capillary stasis could be observed after 24 hours, up to the epidermal layers. In more severe burn wound models, however, as often observed in the clinical situation, these preventive measures, even when associated with a "state of the art" vascular filling and hemodynamic resuscitation, do not succeed in reversing this capillary stasis sufficiently to permit the survival of dermal cells (10).

One of the reasons for this may be found in the sequence of events causing this capillary stasis. During the first hours, the slowing of the capillary blood stream is essentially due to a mechanical compression of the capillaries by edema formation at the tissular end. There, the direct thermal energy overload causes cell lysis and liberation of oncotic substances in the intercellular space, with attraction of fluids from the capillary vascular bed, and elevation of the capillary blood viscosity (11). This corresponds to the first phase observed by Zawacki. At a certain point, this will induce rouleaux formation of the red blood cells, progressive desaturation of their hemoglobin and progressive hypoxia in the capillaries adjacent to the initial burn injury. Consequences of this hypoxia, such as endothelial cell swelling and initiation/propagation of inflammatory reactions will increase the permeability of the capillary wall and augment the edema formation in these zones (12, 13). The causes of edema formation will thus be progressively shifting from initial extracapillary (increased oncotic pressure and hence increased afterload) to local structural defects (augmented capillary permeability and endothelial cell damage).

A key factor in both the endothelial cell damage and the initiation of the various inflammatory cascades (complement activation, activation of arachidonic acid cycle, coagulation cascade, activation of polymorphonuclear leucocytes) seems to be hypoxia-induced oxygen free radical (OFR) formation (14, 15, 16, 17).

In fact, the OFR mediated reactions taking place in the vicinity of the burn wound show striking similarities with those observed in most ischemia-reperfusion models (18). As in those, hypoxia induces OFR formation by means of at least two mechanisms: the conversion of Xanthine-Reductase (X-R) to Xanthine-Oxidase (X-O) (15, 19), and the increase of the natural Superoxide Radical spill by the reduction of the enzymes of the Electron Tranfer Chain in the mitochondria of the endothelial cell (20). The increased production of Superoxide Radical initiates an auto-aggravating process, with the leucocytes playing a key role in continuing OFR production (21, 22). This leads to increasing local tissue damage (by the deleterious action of the various OFR species on all cellular membranes), but may also induce distant pathologic changes related to (pulmonary, hepatic, renal) migration and subsequent translocation of neutrophils, or to increased production of humoral factors (TNFa, IL6...) (14, 16).

Any reduction of the hypoxic capillary and tissue damage would likely reduce not only the final extent of the local insult, but also the risks of subsequent systemic complications in a burned patient.

b. Hyperbaric Oxygen Therapy (HBOT) and Piracetam in the treatment of burns

Since 1965, the possible beneficial influence of HBOT on burn wound healing has been suggested (23). Because of a lack of randomised prospective clinical trials and financial and/or practical constraints, the therapeutic use of oxygen under pressure has not yet gained widespread acceptance, on the contrary.

There have been, however, a considerable number of experimental reports that document the effects of HBOT when used in the acute phase after the burn injury.

• a decrease of the amount of plasma extravasation (25% vs. 41%) in dogs, submitted to a 40% TBSA 3rd degree burn (24),
• an acceleration and more complete restoration of the capillary permeability (measured by the Chinese Ink infusion technique) in a rat model of 5% TBSA partial thickness burn (25),
• a preservation of the tissue ATP levels in zones adjacent to the burn wound (26),
• a decrease of edema formation and exsudation rate in and around a (5mm diameter) experimental partial thickness burn wound in a human model (27).

These possible effects would be related to

• a generalized precapillary vasocontriction, hyperoxia-induced, diminishing the blood flow through the damaged capillaries (28),
• an increase of the quantity of oxygen transported per unit of blood, by physical dissolution of oxygen in plasma (up to 5ml/100ml plasma) (29),
• an increase of the intracapillary pressure of oxygen, resulting in an increase of the pericapillary diffusion distance of oxygen (30),
• a possible increase of the plasticity of the red blood cells, diminishing the capillary sludge (31).

A number of clinical reports of the use of HBOT exist, that seem to confirm these experimental findings. Notably, a reduction in resuscitation fluid requirements, in the needs for surgical interventions, in duration of hospital stay and in total hospitalisation costs, has been noted in patient groups, comparable in age, type of burn, and TBSA burned (32). These ongoing studies, of a more economical nature, seem to gain importance. They are however subject to criticism because of their retrospective nature and a lack of formal randomisation.

For Piracetam, no animal or human studies are available regarding its use in burns treatment, some being "en route". However, the rheological properties of this widely used drug, together with the complete absence of noticeable side effects, even at extremetly high dosages, warranted its formal evaluation for this field of application.

c. Experimental Setup

Although the influence of HBOT as a therapeutic measure "on its own" has been demonstrated in the experimental setting, few animal studies have been done to evaluate the supplemental benefit of HBOT to a classical burn wound treatment protocol, in preventing the extension of the burn injury.

Therefore, our protocol was designed to resemble a "realistic" burn patient treatment scenario:

• a delay of 3 to 4 hours before initiation of advanced burn wound management
• daily wound dressing changes, with application of an antimicrobial agent
• utilisation of a HBOT protocol that is currently accepted and employed in the ancillary treatment of burned patients (33)
• utilisation of a currently recommended high dosage of Piracetam (200mg/kg b.i.d. IM)

As antimicrobial agent, we have chosen mafenide hydrochloride. Although silver sulfadiazine 1% cream is more commonly used in burn centers throughout the world, its greasy component is incompatible with external high pressure oxygen exposure (risk of explosion). Mafenide, although not commercially available as an aqueous solution, can be obtained in powdery form, and is in our burn center commonly used in a 10% solution, as in the commercially available cream. This unusual pharmacological presentation does not, to our view, affect the validity of the results of our study. Severely burned patients need, in our opinion, to be treated in large multiplace hyperbaric chambers, compressed with air and equipped with advanced intensive care monitoring and life support apparatus. In this "intensive care" hyperbaric chambers, greasy wound dressings are not prohibited since the external environment of the patient consists solely of compressed air, the high pressure oxygen being breathed or administered via an isolated breathing circuit.

For this study, no hematological or serological parameters have been studied, for the burn wound inflicted was small (5% TBSA) and would not routinely need important intravenous fluid resuscitation. Also, the risk of distant complications is, in this type of injury, virtually non-existant. Lung tissue biopsies, taken from animals of preliminary groups after completion of the study period, showed no gross pathologic alterations (data not shown) in either group. Any serologic alterations would be likely to be either unmeasurable, or of no clinical significance in this burn wound model.

d. Results

HBOT and Piracetam were both able to decrease the amount of (epi)dermal cellular destruction, as well as the degree of inflammatory reaction (dermal leucocyte infiltration), when applied early after the burn infliction. This represents an added benefit when compared to a "classical" burn wound treatment only. Some reservations have to be made, however, as to the interpretation of these results.

• It is not known how big a fraction of skin appendages needs to be preserved to ensure a spontaneous burn wound healing. The difference in appendage destruction is significant but small. Whether this will result in faster healing of the burn wound, is impossible to appreciate from this study.
• The same remark can be made for the percentage of destruction of the surface epithelium. This destruction is, obviously, mainly induced by the direct thermal energy directed to these cells. The fact that HBOT or Piracetam, either via an increased availability of oxygen or by some other mechanism, can preserve a bigger portion of these cells, is interesting, but here again, the difference is very small, and the clinical importance is questionable.

The decrease in polymorphonuclear leucocyte infiltration is the most striking observation. Being admittedly only an imprecise indicator of the extent of the inflammatory reactions that are taking place, neutrophil adherence to the capillary wall, followed by rolling and translocation, is one of the earliest and most easily observable signs of their activation (17, 22, 34, 35). It seems that both HBOT and Piracetam are able to significantly reduce this leucocyte migration.

Conclusions

This study addressed the possible benefits of HBOT and Piracetam when added to the burn wound treatment - from a morphological, descriptive point of view. No information was obtained as to the final clinical consequences of these ancillary treatments, because animals were sacrified before wound healing. However, the effects of Piracetam, but more notably of HBOT on the degree of inflammatory leucocyte response are important, and warrant further investigation. A biochemical study, with a more important burn injury and subsequent serological measurements, as well of its effects on OFR production, will therefore be undertaken. In the mean time, this study somehow adds support to the claims of HBOT of having a place in the combined early management of the burn injury.

(Supported by a grant from the Brussels Capital Region Energy Department, Belgium)

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HYPERBARIC OXYGEN THERAPY IN THE TREATMENT OF BURNS:
EVALUATION OF SYSTEMIC LIPID PEROXIDATION AND
ACTIVATION OF OXYGEN-RADICAL DEPENDENT INFLAMMATORY REACTIONS

P.Germonpré (1), I. Van Renterghem (1), P.Reper (2), L.Duinslaeger (2), A.Vanderkelen (2)
(1) Center for Hyperbaric Oxygen Therapy, Military Hospital Brussels
(2) Burn Center, Military Hospital Brussels

Introduction

In a previous study, we demonstrated the ability of Hyperbaric Oxygen Therapy (HBOT) to prevent at least partially the deepening of an experimental burn during the first days after injury. However, most of the distant complications of major burns seem to be related to the generation of Oxygen Free Radicals (OFR). Therefore, before proceeding to a clinical human study, we wanted to evaluate the possible toxic effects of HBOT in a more extensive burn injury.

Methods

A double-blind prospective study was undertaken. Male Wistar rats were subjected to a 40% TBSA thermal burn or sham burn by submersion, and were resuscitated with intraperitoneal Hartmann solution. After randomisation, half of the burned animals received one HBOT session (60 minutes, 2 ATA) starting 30 minutes after the burn. The animals were sacrificed at 30 minutes (sham burn and control burn groups), 120, 240 or 360 minutes (all groups). Lipid peroxidation products were measured by means of an optimised fluorometric measurement of Malondialdehyde (MDA). Systemic inflammation was evaluated using standard Complement Hemolytic Activity (CH50) and Tumor Necrosis Factor alpha (TNFa).

Results

There was a significant difference in the mortality rate at time points 240 and 360: 28% in the control burn group vs. 11% and 7% in the sham burn groups and HBOT groups respectively. The serum MDA content in the HBOT treated rats was similar to that of the sham burned rats, at all time points, whereas the control burn rats showed a moderate but significant rise at time points 120 and 240 (p<0.05). The HBOT group showed normal CH50 values at all time points, whereas the control burn group showed a stimulation of complement activation and production (but not depletion), reflected by a rise in CH50 (p<0.05). There was a small and statistically non-significant rise in serum TNFa content (p>0.05).

Conclusions

Early HBOT seems to diminish the generation of lipid peroxidation products after a 40% TBSA experimental burn. It seems moreover to have a positive effect on complement activation, and no significant influence on TNFa production. We conclude that, in this model, HBOT seems a safe therapeutic procedure.

(Supported by a grant from the Brussels Capital Region Energy Department)

SUDDEN DEAFNESS OF UNKNOWN ORIGIN:
SUCCESSFUL TREATMENT WITH HYPERBARIC OXYGEN AFTER A > 7 DAY TREATMENT DELAY

P. Germonpré, M.D.
Center for Hyperbaric Oxygen Therapy, Military Hospital "Queen Astrid"

Abstract

Three case reports are presented of Sudden Deafness of Unknown Origin, that responded favorably to Hyperbaric Oxygen Therapy (HBOT) after treatment delays of 7, 10 and 12 days, respectively. Near-complete remissions were obtained in all three patients, despite initial hearing loss of -60 to -80 dBa on all frequencies before the start of HBOT. All patients were treated at 2.5 ATA in a multiplace hyperbaric chamber. One patient received ancillary normovolemic hemodilution and corticoid therapy. Patient data are presented and an overview of the possible causes in these individual patients is given.

Introduction

Sudden Deafness of Unknown Origin is a diagnosis "per exclusionem". It can be defined as a rapidly (<3 days) progressive, unilateral perceptive hearing loss, often accompanied with tinnitus, in an otherwise healthy patient, where no direct causative agent, predisposing medical condition, or underlying disease process can be demonstrated (1, 2). The medical therapy is in many cases unsuccessfull, and many therapeutic combinations and protocols have been suggested. No consensus exists on the best therapeutic approach. Although Hyperbaric Oxygen Therapy (HBOT) is sometimes advocated, randomised controlled prospective studies are lacking. It is however felt by HBOT clinicians, that the sooner HBOT is instituted, the better the results (3). Institution of HBOT after a delay of more than 7 days is often felt to be of little use. We present three case reports where, despite long delays during which no or insufficient response was obtained with various therapeutics, the association or institution of HBOT resulted in a near-complete recovery of hearing.

Case Reports

A.M., male, 41 y., presents with a left side perceptive hearing loss and low frequency tinnitus, 4 days after an uneventful SCUBA dive well within the limits of decompression (15 msw, 20 min bottom time), and two days after a swimming pool SCUBA training session (2.5 msw depth). At none of these occasions difficulties with ear equalisation were noted. He is a non-smoker, without history of excessive noise exposure. His medical history is without particularities. Tonal audiometry shows a left pancochlear perceptive hearing loss of -80 dBa. Clinical examination shows no signs of vestibular involvement. A left paracentesis at day 3 yields no retrotympanic liquid. He receives no further treatment untill day 6. Tonal audiometry then shows a -75 dBa global deficit. Blood analysis, posterior fossa CT are normal. A treatment with piracetam 12g i.v. per day, and HBOT (2.5 ATA, 90 min) twice daily, is then instituted. A control audiometry after three days shows a near complete remission (MHL: Mean Hearing Loss on frequencies 250, 500, 1000 and 2000 = -10 dBA), with a small dip at 6000 Hz., which remains identical after completion of the 5 days HBOT.

M.M., female, 29 y. presents with a left side perceptive hearing loss, without tinnitus, of the high frequencies (2000, 4000, 8000 Hz: -80dBa). An initial work-up reveals no causative factors. Posterior fossa CT is normal. From her medical history a congenital spherocytosis is retained, which has been asymptomatic after a splenectomy at the age of 12, but with chronically elevated WBC count (13.000 /mm³), and a minor mitral valve insufficiency. Clinical examination is normal, blood analysis shows no signs of active haemolysis. She is treated with betamethason 4mg/day p.o. Despite this, a progression of the hearing loss is noted, and by day +9, a pancochlear loss of -80dBa is present. She is then transferred for adjunctive HBOT. After 5 days of HBOT (2.5 ATA, 90 min, 1x/day), a complete recovery at the low and middle frequencies is noted, with the persistance of a 4000 Hz and 8000 Hz deficit of -60dBa and -40dBa respectively. This remains so after 5 more days of HBOT. There has been no signs of increased haemolysis during HBOT.

D.A., female, 26 y., presents with a perceptive hearing loss and low frequency tinnitus of the right ear, two days after an otherwise uneventful SCUBA dive well within the limits of decompression (15 msw, 35 min bottom time). There has been no barotrauma of the ear. She is a non-smoker, bank employee, who is in good health and takes no medication. The personal and familial anamnesis is without particularities. Physical examination, extensive blood analysis, and posterior fossa CT scan are normal. Tonal audiometry shows an important deficit on all frequencies, with a MHL of -70dBa. She is treated with nasal decongestionants and co-dergocrin mesilate p.o. for 5 days, then for 7 days with normovolemic haemodilution, piracetam 12g i.v. and triamcinolon 3x4mg p.o. without significant improvement. HBOT (2.5 ATA, 90 min) twice daily, is then started for 5 days, without further drug treatment. After completion of HBOT, there is a complete recovery of the high frequencies, and a MHL of -25dBa. 2 weeks after completion, a MHL of -10 dBa is measured, and 6 months later, this is confirmed.

Discussion

Pathogenesis of SD: In cases where no external or internal cause could be determined, the exact pathogenesis of the hearing loss is not known. Possible mechanisms include micro-thrombo-embolism, arterial vasospasm, perilympatic hypertension, viral infection. Whatever the cause, the consequence is in most cases edema formation, with cochlear arterial supply compromise. The final end-point is endo-cochlear hypoxia, which leads to degeneration of the hair cells in the Organ of Corti (1). In two of our three patients, initially a decompression illness was suspected, and they were referred to our Center for that reason. The dive profile and the long apparition delay precluded this diagnosis. Inner ear barotrauma could not formally be excluded; however, the presentation delay, the absence of any signs of middle ear barotrauma, and the absence of vestibular symptoms, made this diagnosis unlikely (4). In our third patient (case 2), no signs of increased haemolysis nor increased red blood cell adhesion could be documented. Sudden hearing loss has not been described as a possible complication of congenital spherocytosis. Viral etiology was not formally excluded in these three patients; however, it would appear to have been of little benefit in the management of their sudden deafness, and more of an academical value.

Hyperbaric Oxygen Therapy: Although many different therapeutic protocols have been proposed, placebo-controlled dubbel-blind studies have not yet been able to prove the efficacy of any drug treatment over placebo (2, 5). Spontaneous recovery percentages of as much as 68% have been described (13). Although case reports of spectacular response to various drug treatments have been published after long treatment delays, a good recovery is considered rare if high hearing tresholds persists after the 7th day (6). HBOT is not as widely used as other therapeuticals measures. Reasons for this include lack of disponibility of hyperbaric chambers, a perception by ENT specialists of HBOT being an aggressive and dangerous therapy, and perhaps a lack of clinical and experimental papers on the subject, published in ENT scientific journals. Where HBOT is used, it is generally felt - as with any treatment - that the sooner this treatment is begun, the better the chances of recovery. A reduction of cochlear blood flow but at the same time an important rise of the endo-lymphatic oxygen pressure have both been well documented (5), and this could break a vicious circle of hypoxia-induced ultra-structural changes before reaching the "point of no return" where cellular death is inevitable.

Spontaneous recovery: The problem with all studies on the treatment of sudden deafness is the inability to account for spontaneous recovery rates. Byl (1984) (6) analysed data from 225 cases of sudden deafness and developed a prognostic table, taking into account recognized prognostic factors such as severity of hearing loss, time to treatment, age, slope of audiometry curve, vertigo, hearing loss in the opposite ear, erythrocyte sedimentation rate. Following this (highly estimative) prognostic table, our patients had a chance of recovery of 15%, 15% and 30% respectively. Yamamoto et al. (1994) (7), found the recovery rate on the 7th day of treatment the most useful parameter for predicting the final recovery. Our three patients scored extremely bad, since none had a recovery of more than +10 dBa on day +7. Although we can not exclude a spontaneous recovery, the spectacular fall of the hearing treshold shortly after starting HBOT could not but be noted. In these patients, a sub-critical ischemia of the Organ of Corti's sensorineural elements may have been present, causing the hair cells to reside in a "dormant" state. The mechanisms by which HBOT restored almost normal hearing, are probably mainly related to edema-resolution, oxygen supplementation helping to "bridge the gap" in the meantime.

An interesting observation could be made in case 2. Congenital spherocytosis (CS) has on several occasions been considered an absolute contra-indication for HBOT (8, 9). Because of a lack of solid data on this subject, we chose to treat our patient anyway, providing a close monitoring of hematological parameters. We have observed not the slightest sign of hemolysis, and therefore believe that the contra-indication should be relativized or even lifted in the case of asymptomatic, splenectomized CS patients.

Conclusion

Unfortunately, to this day, there is no reliable method for determining if the hair cells in the Organ of Corti are actually dead or dormant. Evoked oto-acoustic emissions might be clinically applicable in appreciating the chances of recovery (10); however, we are far from able to determine which patients should not be treated aggressively because of high chances of favorable outcome. This report is another illustration of the clinical observation that HBOT, either alone or in combination with other therapies, is an effective treatment in certain patients. Large series (1, 11, 12) have yielded a treatment success rate that is comparable to that of any other treatment, perhaps with less side effects. Even if HBOT is not considered as a primary treatment, it is clear that; as long as no reliable determination is possible of the patients who might not benefit from HBOT, a therapeutic trial is warranted in all patients who have not sufficiently responded to "standard" therapy. HBOT is, like any other treatment used, by no means 100% effective. It should however, in our opinion, not be delayed until little hope exists for further recovery.

References

• Schumann, K., Fischer, B.: Zur Behandlung von Innenohrerkrankungen. Natura Med 1992, 7: 366-385.
• Shikowitz, M.J.: Sudden Sensorineural Hearing Loss. Med Clin North Am 1991, 75: 1239-1250.
• Esteve-Fraysse, M.J., Fraysse, B.: Attitude actuelle face à une surdité brusque. 1st Europ Cons Conf on Hyperbaric Medicine (Intr.Reports), ECHM - ASPEPS, Lille 1994, pp. 137-141.
• Parell, G.J., Becker, G.D.: Conservative management of inner ear barotrauma resulting from scuba diving. Otolaryngol Head neck Surg 1985, 93: 393-397.
• Lamm, K.: Die medikamentöse Therapie der Innenohrschwerhörigkeiten - kritische Anmerkungen. Wien Med Wschr 1992, 142: 455-459.
• Byl, F.M.: Sudden Hearing Loss: Eight years experience and suggested prognostic table. Laryngoscope 1984, 94: 647-661.
• Yamamoto, M., Kanzaki, J., Ogawa, K., Ogawa, S., Tsuchihashi, N.: Evaluation of hearing recovery in patients with sudden deafness. Acta Otolaryngol Suppl Stockh 1994, 514: 37-40.
• Fischer, B., Jain, K.K., Braun, E., Lehrl, S.: Handbook of Hyperbaric Oxygen Therapy. Springer Verlag, Berlin 1988, p.182.
• Kindwall, E.P., Goldman, R.W.: Hyperbaric Medicine Procedures, St.Luke's, Milwaukee 1988, pp.1-2.
• Sakashita, T., Minowa, Y., Hachikawa, K., Kubo, T., Nakai, Y.: Evoked otoacoustic emissions from ears with idiopathic sudden deafness. Acta Otolaryngol Suppl Stockh 1991, 486: 66-72.
• Zennaro, O., Dauman, R., Poisot, A., Esteben, D., Duclos, JY., Bertrand, B., Cros, AM., Milacic, M., Bebear, JP.: Interêt de l'association hémodilution normovolémique-oxygénothérapie hyperbare dans le traitement des surdités brusques à partir d'une étude rétrospective. Ann Otolaryngol Chir Cervicofac 1993, 110: 162-169.
• Dauman, R., Poisot, D., Cros, AM., Zennaro, O., Bertrand, B., Duclos, JY., Esteben, D., Milacic, M., Boudey, C., Bebear, JP.: Surdités brusques: étude comparative randomisée de deux modes d'administration de l'oxygénothérapie hyperbare associée au naftidrofuryl. Rev Laryngol Otol Rhinol Bord 1993, 114: 53-58.
• Weinaug, P. Die Spontanremission beim Hörsturz. HNO 1984, 32: 346-351.

P. Vander Eecken *, P. Germonpré **

*ENT Dept., St.Lucas Hospital, Gent, Belgium
**Centre for Hyperbaric Oxygen Therapy, Military Hospital ‘Queen Astrid’, Brussels, Belgium

Abstract

Labyrinthine Hydrops is until now - to our knowledge - an undescribed cause of vertigo and hearing problems after SCUBA diving. This “Ménière”-like syndrome occurs in divers who have moderate to severe middle ear equalisation problems, but is not associated with true inner ear barotrauma. Instead, the repeated oval window movements and perilymphatic changes of pressure induced by forceful Valsalva manoeuvres, probably induce a reactive rise in peri- and/or endolymphatic fluid production, causing a syndrome of acute vertigo, tinnitus and low-frequency hearing loss in the hours after surfacing. The prognosis seems to be excellent, and eventually only classical anti-vertiginous drug therapy (type beta-histine) is indicated. We present three case reports of divers who suffered from labyrinthine hydrops after SCUBA diving. The pathophysiology, symptoms and various differential diagnostic elements are discussed.

Introduction

With the ever growing popularity of SCUBA diving, the rate of diving-related middle and inner ear injuries likewise has increased. Often, these injuries are related to a lack of knowledge or training. Climatic conditions may be responsible for the higher rate of these injuries in northern countries as opposed to those countries that possess more tropical diving waters. Several divers presenting with a Ménière-like syndrome, occurring minutes to hours after surfacing, will be presented. Some of these had been treated in the past for inner ear decompression sickness (IEDS), presenting the same triad of symptoms: low frequency hearing loss, tinnitus and vertigo. These diving injuries occurred after relatively innocuous dives, and have been classified previously as “undeserved” IEDS. A common denominator in these episodes was a moderate Eustachian tube dysfunction, with usually an interruption during the descent due to ear equalisation problems. All symptoms cleared over a period of 5 to 6 days, and the course of disease seemed to be favourably influenced by a beta-histine treatment, as in Ménière’s disease.

Subjects and methods: case reports

A female diver, 24 years old, makes a single dive to 15 msw for 35 minutes (bottom time 25 minutes) in a lake, at a water temperature of 5° Celsius. She has at the time a moderate viral rhinitis, and has not taken any medication before the dive. The dive is uneventful, except for an incomplete equalisation of the right ear, and a continuous feeling of pressure (no pain) during descent and bottom stay. A few minutes after surfacing, this pressure seems to increase, and she experiences a feeling of instability, unchanged by position changes (ie. supine position). There is a moderate nausea. Only 24 hours later, she is examined. Clinical examination is normal except for a slight congestion of the nasal mucosa. Micro-otoscopic examination shows no signs of middle ear barotrauma. Tympanometry is normal. Pure-tone audiometry reveals a sensorineural hearing loss of -20dB at frequencies 125, 250 and 500 Hz at the right side. Vestibular testing, including electronystagmography, is normal. She is in possession of an audiometry taken a few months before the accident, which was completely normal. She is treated with beta-histine 3x16mg daily. All symptoms disappear within 3 days. A control audiometry shows a complete hearing recovery. The same patient presents 5 months later, 5 days after a similar episode of instability and sensation of fullness in the right ear, after an equally innocuous dive. She feels already much better at the time of the consultation, and pure-tone audiometry is normal. No therapy is given. She reports complete resolution of the symptoms only after 14 days of relative rest.

A healthy young male diver, 20 years old, makes a single dive to 17 msw, total dive time 40 minutes (bottom time 14 minutes), in the sea at a water temperature of 13° Celsius. The dive is uneventful, except for moderate pain in the right ear due to difficulties equalising. After the pain has cleared, the dive is continued with a slight feeling of pressure in the right ear (no pain). A few minutes after surfacing, a feeling of “sea-sickness” occurs, with nausea and a sensation of fullness in the right ear. Four hours after the onset of symptoms, he is examined. Clinical ENT examination reveals a retracted ear drum on the right side, without other signs of middle ear barotrauma. Tympanometry confirms a hypopressure in the right middle ear (-200 dapa, peak value 0.4ml vs. -85 dapa, peak value 0.6ml in the left ear). Pure tone audiometry shows a sensorineural hearing loss of -20 dB in the low frequencies only. Electronystagmography shows a hyperreactive right labyrinthine system (caloric tests). He is treated with beta-histine 3x16mg daily. All symptoms disappear within three days. Control audiometry shows full hearing recovery.

A healthy male diver of 48 years old, makes his second dive of the day. The first dive was 20 msw, 56 minutes total dive time (of which 15 minutes spent at depth), the surface interval was 4 hours. He now dives to 16 msw, makes multiple ascents-descents between 16 msw and 5 msw, and surfaces after 25 minutes. The water temperature is 25° Celsius. Both during the first and the second dive there are some difficulties in equalising the middle ear pressure on the right side. Strainful Valsalva manoeuvres are used. There is moderate pain. Twenty minutes after surfacing, he experiences rotational vertigo, and a sensation of fullness of the right ear. There is nausea but no vomiting. He is examined some hours after the onset of these symptoms. Clinical examination reveals a Stade 1 barotrauma of the right ear drum. Tympanometry shows hypopressure in the right middle ear (-180 dapa, peak value 0.6ml vs. -30 dapa, peak value 0.8ml in the left ear). Pure tone audiometry shows a sensorineural hearing loss in the low frequency range to -20 dB. Electronystagmography is normal. A treatment with oral decongestive drugs (an antihistaminic drug plus ephedrine) is started, with oral corticotherapy. The otoscopic examination returns to normal within 5 days, but the vertigo persists until the 10th day. The pure-tone audiometry shows a hearing recovery only after 3 weeks.

Discussion

Ménière’s disease was first described by P. Ménière in 1861. It consists of periodic “attacks” of vertigo, tinnitus and low frequency hearing loss. It occurs preferentially in females in their forties, and is often triggered by stress, alcohol, caffeine use. The attacks last minutes to hours; their is complete recovery at first. With recurring episodes however, the low frequency hearing acuity is progressively destroyed.

The pathophysiology of Ménière’s disease consists of a quantitative disturbance of the electrolyte concentration between endolymphatic and perilymphatic fluids, resulting in an osmotic pressure rise in the endolymphatic system (high potassium concentration). This pressure rise causes a rupture of Reissner’s membrane, usually at the apex of the cochlea (helicotrema), seldom in the basal turns, in the sacculus or utriculus. Endolymphatic and perilymphatic fluids mix, and potassium penetrates in the intercellular space. The rise in potassium concentration provokes a depolarisation of the afferent neurones of the acoustic and vestibular nerve, and thus gives rise to the typical symptoms (Fig. 1).

The treatment consists in the restoration of ionic balance and volumes (acetazolamide, beta-histine), and anti-emetic drugs. In severe cases, a vestibular nerve section has been proposed. The efficacy of a translabyrinthine sacculotomy (in order to relieve the pressure in the endolympathic sac and duct) is heavily disputed. Over years, there is a progressive decline in the hearing acuity. The vertigo is usually well controlled (central compensatory mechanisms).

Figure 1: Pathogenesis of Ménière’s disease (Becker et al.)

The divers we describe in this paper presented with Ménière-like symptoms: sudden onset of tinnitus, vertigo (rotational at first, with a remaining instability after a few hours) and low frequency hearing loss. These symptoms occurred a few minutes to a half hour after surfacing from the dive. All cases had experienced moderate Eustachian tube dysfunction during the dive, and reported moderate pain or sensation of fullness in one ear during the dive.

Inner ear decompression sickness (IEDS) was estimated to be unlikely in all cases, because of the shallow depth and/or short dive times. All cases were nevertheless investigated for patency of the Foramen Ovale (PFO), by means of trans-esophageal echocardiography. Cases 1 and 2 had no PFO, case 3 had a type 1 PFO (less than 20 bubbles). Cerebellar decompression sickness (DCS) was also excluded, because of the dive profiles and the absence of other symptoms of DCS. None of the divers breathed oxygen as a first aid measure. Inner ear barotrauma (IEB) was excluded because of the onset of symptoms only after the dive, and because of the very mild middle ear barotrauma. Also, hearing loss in IEB typically affects the high frequencies, because of a perilymphatic fistula or endo- or perilymphatic bleeding. IEB would however have to be suspected in case of persistent (3 to 5 days) rotational vertigo, even with normal otoscopic findings. Finally, alternobaric vertigo should be considered. Although in two of the 3 cases, unequal middle ear pressures could be demonstrated, this diagnosis seems improbable because of the sensorineural hearing loss (no air-bone gap) and the persistence of symptoms over a period of days even with local or systemic nasal decongestive drugs.

We hypothesise that repeated high-amplitude tympanic movements (strained Valsalva manoeuvres) or a continuous pressure-induced inward protrusion of the tympanic membrane and thus, amplified by the ossicle chain, of the stapes footplate into the oval window, causes a pressure rise in the perilymph system. This perilymphatic hyperpressure would then cause a reactive hypersecretion of endolymphatic fluid. Upon surfacing, the perilymphatic pressure returns to normal, and a hydrops of the endolymphatic system will develop. Because of the delay between perilymphatic hyperpression and reactive endolymph secretion, a lag-time may exist in the appearance of the symptoms. A rupture of Reissner’s membrane may occur, although it is possible that the symptoms are only due to an increased diffusion of potassium ions into the perilymph.

Treatment with beta-histine resulted in rapid resolution of symptoms in the first two patients, whereas no treatment or treatment with nasal decongestive drugs did not provide complete relief until after 2 to 3 weeks. As a precaution, beta-histine was continued for 2 to 3 weeks, and diving was suspended for 6 weeks. Further and more detailed (e.g. NMR) studies of future case reports will have to elucidate the exact pathogenesis and optimal treatment of this syndrome.

Conclusion

Diving with rhinitis, sinusitis or Eustachian tube dysfunction is not recommended. However, most divers do not abort a dive or series of dives for moderate Eustachian tube problems. Strainful Valsalva manoeuvres are common practice for many divers, and will even be more common during cold water dives. Even if the ear can finally be “cleared”, a mild middle ear hypopressure may persist during the dive.

A syndrome of vertigo, tinnitus and hearing loss, after a dive, often presents a difficult diagnostic problem. Inner ear decompression sickness and inner ear barotrauma require quite different treatment regimens, with a quite different degree of urgency.

We presented three case reports of a “new” syndrome, with an excellent prognosis (at least on the short term), and a effective treatment. Over the past few months, three more cases were diagnosed, one of which had in the past undergone repeated hyperbaric treatment for suspected decompression sickness. Careful analysis of the accidental dive, the symptoms and their time course might have diagnosed this case earlier.

We propose to add “endolymphatic hydrops” to the list of differential diagnoses of acute vertigo and hearing loss after a SCUBA dive.

References

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2. Farmer, J.C. (1982). Otologic and paranasal problems in diving. In: The Physiology and Medicine of Diving. P.B. Bennett and D.H. Elliot (Eds.). Best Publishing Co., San Pedro, CA, pp. 507-536.
3. Shupak, A., I. Doweck, E. Greenberg, C.R.Gordon, O. Spitzer, Y. Melamed and W.S. Meyer (1991). Diving-related inner ear injuries. Laryngoscope 101: 173-179.
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