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Acute Brain and Cardio-Respiratory Dysfunction After Blast/Blunt Injuries: The Life-Preserving Effects of Hyperbaric Oxygenation

Gennady G. Rogatsky and Avraham Mayevsky

The Mina & Everard Goodman Faculty of Life Sciences and the Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel

IV. CAPABILITIES OF HYPERBARIC OXYGENATION

In the view of the above, one of the goals of the present work is to analyze the possibilities of applying hyperbaric oxygenation - HBO₂ the most powerful method of oxygen supply to the organism known today) in order to replenish the acute progressive oxygen deficit in the organism, emerging after blast injury. In pursuing this goal, we rely both on the results of the (quite moderate) experience of using HBO₂ treatment for blast injury and the results of its use in other critical situations caused by blunt chest injury, blunt head injury and other conditions usually present in severe blast injury.

In accordance to the present state of knowledge, the use of HBO₂ treatment of blast injury pursues the following aims: a) reaching an immediate reduction in air bubble size based on Boyle’s law, b) increasing the level of internal pressure of oxygen in the hyperbaric chamber to ensure the rise of partial oxygen pressure in the tissues (through oxygen diffusion from the blood to the tissue).¹⁶¹

Since gas embolization has long been regarded a “classical” indication for HBO₂ treatment, the same approach has been considered as a possible method to eliminate blast-lung-injury-induced air embolization.^{45,56,57,80,85,105,160,161,201,202,232} Animal experiments showed that when hyperbaric therapy was maintained for 29 hours, the blast mortality was reduced from 60% to 0%.⁵⁶

Despite the fact that many contemporary instructions, manuals and information bulletins recommend the use of HBO₂ for “some cases of blast lung injury”,^156,218-220 in fact, concrete original investigations of this problem were mainly conducted in the 1970s, whereas in the available literature of a later period data on the relevant investigations are not to be found. In this regard, it is necessary to note the works of Damon and Jones⁵⁷ and Weiler-Ravell et al.,²³¹ cited in all the works dedicated to the problem.

The former experimental work on different mammalian species (guinea pigs, rabbits, beagles) includes convincing evidence for a significant increase (as compared to control) in the survival time of the animal groups subjected to HBO₂ after reconstituting non-penetrating impact trauma to the thorax. Data analysis from investigations during the care of victims found in critical conditions due to a strong underwater explosion wave, enabled the authors to recommend the use of HBO₂ as early as possible after the explosion.²³¹

Elimination of air embolization and, as a result, of acutely developing respiratory distress were considered by the authors as the main purpose of HBO₂ therapy in these cases, which can be regarded as the most favorable emergency measure, to be followed later by a more extensive and definitive treatment in a major hospital equipped for such contingencies.

As has been noted above, severe blast injury is often a multi-organ injury, accompanied by marked pathophysiological perturbations, the most dangerous of which (with respect to survival) are the impairments in the vital organs. In the past 20 years, there have been conducted investigations in the field of emergency hyperbaric medicine whose results have a direct relevance to the problem under consideration, namely, the management of blast injury.

In the same years, modern methodological and technological conditions have been developed for obtaining basic data on the pathophysiology of blunt chest injury and head injury (see the section “Pathophysiological changes”). Therefore, it appears justified to study the effects of HBO₂ exposure on the dynamics of major life-determining physiological parameters in patients, as well as in corresponding experimental models.

As indicated above, previous investigations showed that severe blunt chest injury (BChI) is accompanied by an early cardio-respiratory dysfunction.^{107,142,168,175} This dysfunction led to a drastic decrease in oxygen delivery, associated with poor outcome.¹⁶⁸ Mortality increases to an even greater level upon combined BChI and head injury, which often occur in the most severe cases of blunt trauma.^23,192

We have conducted clinical observations of severe BChI in patients that underwent HBO₂ therapy in the course of their management.^177,182 All the patients suffered 4-12 rib fractures with subsequent contusion of the lungs. Pneumothorax was diagnosed in 10 patients and hemopneumothorax in 15 patients at the time of admission; two of the latter underwent surgery to control bleeding.

Twenty patients were in a state of traumatic hemorrhagic shock at the accident site. Twenty-two patients also had injuries in other parts of the body (brain, abdomen, pelvis and long bone), but BChI was the major determinant of the patients’ general condition.

Within the 24-72 hours following BChI, all 26 patients developed arterial hypoxemia during the initial administration of conventional treatment and they comprised the cohort of study. In the retrospective analysis, the patients were divided into three groups according to their outcome and the therapy they received: Group A consisted of 4 survivors who were treated by conventional therapy only, Group B consisted of 14 patients who died after having been treated by conventional therapy only, and Group C consisted of 8 survivors who were treated by a combination of conventional therapy and HBO₂ therapy.

The management of patients with BChI at the time of admission consisted of resuscitation of circulation and breathing. According to the standard protocol, the patients were resuscitated by a transfusion of a solution of crystalloids and colloids, blood (or blood products) as clinically indicated, nasotracheal or endotracheal intubation as necessary, supplemental inspired oxygen, correction of acid-base changes in the blood, resolution of pneumo- and/or hemopneumothorax, inotropic support (as necessary), and analgesia. Mechanical ventilation was used when indicated in cases of severe and resistant hypoxemia.

All hyperbaric treatments were started 1-2 h after BChI was detected and were performed in a monoplace chamber. The standard protocol for HBO₂ exposure was 1.6-2.0 ATA, 40-60 min daily for 4-15 consecutive days, and this was adjusted according to the progress of recovery. Cardiac output index (CI) and stroke volume index (SVI) were measured by a non-invasive impedance cardiography technique^103,123 using corresponding standard formulas.197 Arterial blood gas values were measured as well (ABL-330, Radiometer). The measurement of all the parameters was usually simultaneous and performed 1-3 times daily.

In order to compare cardio-respiratory changes in patients after BChI, we distinguished between three phases. The first phase, lasting for up to 24 h from the moment of trauma, was marked by cardio-respiratory instability (sometimes with very severe changes in homeostasis) and rehabilitation was induced by intensive care treatment. In the 2nd phase, beginning at days 2-4 and continuing up to 26 days, we observed signs of the appearance and development of acute cardio-respiratory dysfunction (ACRD).

Phase 3 continued for up to 2 days: it was during this phase that the rapid and fatal worsening of cardio-respiratory parameters occurred among the non-survivors. In contrast, a relatively stable state to a near-normal level of cardio-respiratory parameters was attained in the surviving patients. Phase 3 usually continued until the end of the stay in the ICU.

Table 1 presents the characteristics of these dynamic changes. In all the groups, the 1st phase is characterized by a profound reduction in the mean values of the cardio-respiratory parameters (PaO₂/FiO₂ ratio, PaO₂, SVI, CI) and tachycardia. The 2nd phase is characterized by a tendency towards recovery of all these parameters in groups A and C, but not in Group B. This tendency was more pronounced in Group C, for which a statistically significant increase in these mean parameter values was apparent already in the 2nd phase, as compared to the measurements in the 1st phase.

The 3rd phase in Groups A and C is characterized by a subsequent recovery of these parameters to a normal (or near-normal) level. As a result of these tendencies, the mean values of the parameters in the 3rd phase were significantly higher than those in the 1st phase (PaO₂/FiO₂ ratio, PaO₂, SVI) and even in the 2nd phase. However, in spite of these tendencies, only in Group C did we observe a complete normalization in the means of all the measured cardio-respiratory parameters in the 3 phases.

There were different qualitative changes in Group B. After the initial reduction of the parameters in the 1st phase, the cardio-respiratory function was subsequently worsened in the 2nd and 3rd phases. In fact, the reduced means of the PaO₂ and PaO₂/FiO₂ ratio levels – significantly lower in the 3rd phase than in the 1st and 2nd phases – yielded a critically lower mean level of SVI. Compared to the 1st phase, in the 2nd phase, only CI increased for a while due to tachycardia. The extremely low levels of PaO₂ and SVI in the 3rd phase were ultimately fatal for these patients.

As a result of all the above tendencies, the difference in the mean values of SVI, PaO₂ and PaO₂/FiO₂ ratio in Group A and more so in Group C, took on increasing importance when compared to the same parameters in Group B, becoming maximal in the 3rd phase (p<0.001). The mortality rate in the integral group treated by conventional therapy (Groups A+B) was 77%, and 0% in Group C (conventional and HBO₂ therapy).

The data presented in Table 1 testify to the development of ACRD after BChI, characterized by a reduction not only of pulmonary gas exchange but also of heart pump function. When considered together with the PaO₂/FiO₂ ratio and the PaO₂ value, the SVI is a highly prominent marker, especially in the group of patients with a fatal outcome for whom the intensive therapy failed to restore and stabilize the cardio-respiratory function.

In analyzing the clinical course in Group C, it appears that the cardio-pulmonary resuscitation in the patients with a poor cardiac function who were treated by HBO₂ was quite similar to that of group A. Moreover, the statistically significant increase of PaO₂/FiO₂, PaO₂ and SVI, that was apparent already in the 2nd phase relative to the 1st phase, suggests that the reversibility in Group C was more pronounced than in Group A.

As a result, patients treated by a combination of conventional and HBO₂ therapy in the 3rd phase can be expected to reach a full normalization of the mean levels of these cardio-respiratory parameters. It is also noteworthy that the absence of mortality and morbidity in 8 patients treated by HBO₂ may indicate that HBO₂ exposure was especially suitable for patients with a poor cardiac function following BChI and its complications.

The mechanisms producing the positive effect of HBO₂ on patients may include the powerful anti-hypoxic potential of this supportive therapy, capable of effectively correcting the disorders induced by acute tissue oxygen deficit.^{25,100,112,171} Accordingly, by the elimination of progressive arterial and tissue hypoxia, which can appear as a “physiologic depressant” of the heart,³² the use of HBO₂ makes it possible to prevent, or at least delay, the acute progressive disturbances in myocardial contractility.

This conclusion appears to be supported by the data showing the restoration of hypoxic myocardial contractions after treatment with HBO₂ in humans^71,207 and even an increase in cardiac contractility in healthy animals.^69,205 Thus, we can assume that the significant recovery of SVI following HBO₂ administration may create a potential for normalization not only of CI levels, but also of lung gas exchange, achievable by this pathogenetic approach to ACRD therapy.

We believe that the state of cardiac function is a determining factor in victims who had undergone severe blunt trauma. The elimination of the cardiac component of hypoxia in these victims was no less important (perhaps even more) than the elimination of the “pure” pulmonary component, because the restoration of the necessary level of SVI and CI effectively solved the problem of adequate oxygen delivery to the tissues.

The data in Table 1 clearly show that the recovery of respiratory function in Groups A and C was accompanied by a tendency of SVI increase in the 2nd and 3rd phases. We propose that by an adequate therapy, the “vicious circle” of interconnected acute deteriorations of respiratory and cardiac functions can be interrupted, and that the main goal of such a therapy should be the elimination of hypoxic and circulatory hypoxia. Therefore, HBO₂ should be considered as a first-time treatment by virtue of its demonstrated capability to improve the cardio-respiratory function.

It is necessary to note that in the presented work, in approximately half of the cases (54 %), the victims demonstrated signs of closed head trauma of different degrees of severity (including the victims in group C). This fact did not constitute a counter-indication for the use of HBO₂ therapy.

As the literature analysis shows, a certain number of clinical and laboratory studies have reported the results of HBO₂ application in traumatic brain injury. In particular, these studies indicate that HBO₂ therapy mitigates the increase in intracranial pressure (ICP) and brain edema,^139,171,206 enhances brain tissue metabolism,^60,100,172 and improves mortality parameters.^10,169,171 However, we have not encountered in the literature any data concerning the influence of a maximally early application of HBO₂ therapy on the survival of subjects with a severe mechanical brain injury.

As it is known that head injury often accompanies BChI and can play an important role in the pathogenesis and poor outcome of severe blunt chest injury,^16,192 we will also present here some of our data on the effects of HBO₂ therapy on the survival and several brain parameters in rats at an early phase of severe traumatic brain injury.

Figure 4 provides an example of HBO₂ application as a resuscitation method in a rat model of severe fluid percussion brain injury.¹⁷⁹ This figure shows that TBI leads to the cessation of spontaneous respiration. After 2 minutes of artificial respiration, the hyperbaric chamber was washed with 100% O₂ and compressed to 50 psi. NADH oxidation occurred during the compression period. NADH remained oxidized for the duration of the decompression period, and ECoG was seen to recover along with the resumption of spontaneous respiration. .

The purpose of our recent work¹⁸⁰ was to determine whether HBO₂ treatment might have a therapeutic effect on intracranial pressure (ICP) dynamics and survival after severe TBI in rats, using FPBI model. Changes in ICP levels were analyzed every 30 min during an 8-h monitoring period after trauma and at the end of the experiment (20 h). The control (A) and experimental (B) groups consisted of 7 and 4 rats, respectively. Group B was subjected to 1.5 atmospheres absolute (ATA) 100% oxygen for 60 min beginning 2 h after FPBI.

No significant differences in ICP were noted between groups A and B before and after HBO₂ treatment until 3.5 h after the trauma. At 4 h, for the first time, the difference became significant (P=0.025, n=11) and remained significant (P<0.05) for all measurement points until the end of monitoring, when the mean ICP values reached 37.17±14.25 and 20.25±2.63 mm Hg in groups A and B, respectively. Linear approximation models showed different trends (bl=3.80±0.23; r2=0.65, P<0.001 and bl=1.56±0.25; r2-0.77, P<0.001) for groups A and B, respectively.

Covariance analysis confirmed significant differences between slopes for groups A and B (F=148.04; P<0.001; df=2.177), i.e. a significant difference in the mean rate of ICP elevation. By the end of the experiment, 2 out of 7 rats from group A had died, but none from group B. We conclude that the application of HBO₂ during the early phase of severe FPBI significantly diminished the ICP elevation rate and decreased the mortality level.

The mechanisms of HBO₂ therapeutic effect under the above conditions can be related to the hyperbaric delivery of the urgently needed oxygen to the tissue, and also to the subsequent sustained improvement in the tissue metabolism of the traumatized brain, as shown by Rockswold et al.¹⁷² and Daugherty et al.⁶⁰

However, the particulars of the protective effect of HBO₂ in the traumatized brain remain unclear. Nevertheless, in the case of TBI, this protective effect may be clearly seen by the ICP dynamics. A clear distinction in adaptation efficiency was evident between groups A and B beginning at 4 h after the trauma (i.e. 1 h after HBO₂ treatment in Group B), owing to the mechanisms noted above.

In a recent report, Rockswold et al.¹⁷² noted the efficiency of the earliest possible HBO₂ treatment for achieving a positive outcome in acute TBI, including TBI with subsequent intracranial hypertension. Nevertheless, in actual practice, therapy is only started at least 9 h (an average estimate 23±2 h) after the trauma, i.e. during the stage when the probability of developing the secondary hypoxic insult is already high.^222,240,244

A definite positive effect was achieved in our studies under much earlier HBO₂ application (approximately 2 h after severe trauma). These results may indicate the efficacy of the early administration of HBO₂ after such traumas. The earliest possible HBO₂ application has already been recommended in cases of severe carbon monoxide poisoning.^70,90

Such a treatment may also be reasonable after severe TBI (during emergency care), compensating for or neutralizing severe oxygen deficiency caused by the drastic decrease in cerebral blood flow^29,129 and acute respiratory dysfunctions.^162,240

Experimental studies have demonstrated the principally important fact of the significant increase in PbtO₂ after applying hyperbaric oxygenation (HBO₂), in rats with TBI induced by fluid percussion. It is important to note that, after HBO₂ treatment, there also occurred the restoration of the mitochondrial activity that had been reduced by brain trauma.⁶⁰

In a recently published paper, the same group of researchers indicated that injured animals treated by HBO₂ showed significant improvements also with respect to cognitive recovery and reduced hippocampal neuronal cell loss.²⁴² The application of PbtO₂ monitoring in these works, allowed the authors to determine a clear correlation between the level of oxygen supply to the traumatized brain tissue and the effect of HBO₂ on the dynamics of brain metabolism recovery.

As a consequence, the recovery of the tissue metabolism might provide the conditions necessary for the earlier clinical stabilization of the patient’s state and may diminish the risk of unfavorable outcomes of TBI.

In conclusion, the application of HBO₂ at an early phase of severe FPBI can significantly diminish the ICP elevation rate and decrease the mortality level. Future studies should determine the optimal onset time and regimen of HBO₂ exposure in TBI therapy.

Thus, the results of the above investigations concerning HBO₂ treatment of traumatic brain injury (head injury) may be used to develop and perform the management of victims with secondary and tertiary blast injury, as it was performed in the care of victims with combined blunt chest injury and head injury. In addition, while presenting the data on the use of HBO₂ therapy for head injury, it is apparently worth noting the beneficiary results of HBO₂ treatment in cases of intra-cerebral hemorrhage, both in clinical observations^{109,110,116,122}, and in experimental models^153,237

Hemorrhage is a constant component of severe traumas. This also fully refers to blast injury, where the blood loss can reach significant volumes.^65,161,164 In this relation, there are important data regarding the use of hyperbaric oxygen as an effective protector against severe hemorrhagic shock^{2,22,82,83,195} and against blood loss anemia.92-94,234 Thus, Hart et al.93 by the correction of exceptional blood loss anemia reported 70% survival in 26 patients who received HBO₂ after losing more than 50% of their circulating volume.

Boerema et al.²⁵ demonstrated the principal possibility of life-maintenance in animals with hyperbaric oxygenation under conditions of complete blood replacement with physiological solution (saline). Thanks to these investigations, the Undersea and Hyperbaric Medicine Society (UHMS) have since many years recommended treatments of exceptional blood loss anemia by up to 3 ATA, for a 2-4 hour period, 3-4 times a day.⁸⁹

Based on the presented data, there are grounds to assume that under severe blast lung injury (as well as under blunt chest injury) the use of HBO₂ therapy ensures not only (and/or not primarily) the protection from air embolization, but also the maintenance of cardio-respiratory function, as well as resistance to acute blood loss anemia of the victims.

When evaluating the protective effects of hyperbaric oxygen in the organism under severe trauma conditions, it is necessary to point to yet another property which was described by Imperatore’s group.^54,106,127 These authors presented evidence for the preventive effects of HBO₂ in a rat model of systemic inflammatory response (SIR) and circulatory shock induced by zimosan injection.

Under HBO₂ exposure of zimosan-treated rats, the survival increased along with the reduction in peritoneal inflammation. HBO₂ (2 atmospheres absolute) was effective in preventing the development of multiple organ failure, manifested by damage of the lungs, liver and small intestine, after the intra-periotoneal administration of zimosan.

These results, in fact, confirm our earlier data regarding the pronounced protective action of HBO₂ on the development of acute respiratory dysfunction in rats as a result of intra-pulmonary injection of oleic acid. The performance of only one session of HBO₂ treatment significantly reduced, in the experimental group, the intensity of spreading arterial hypoxemia and the mortality rate as compared to the control group^176,178 (Fig. 5).

Corresponding to the above-said functional differences in the investigated groups, there were also noted structural (inflammatory) changes, whose development was drastically inhibited in the HBO₂-treated group. Clinical observations also showed that pre-treatment with hyperbaric oxygen can reduce systemic inflammatory response after cardio-pulmonary bypass.⁶

The scope of investigations on the subject is, presently, rather small. Nevertheless, the obtained results indicate the great promise of developing and applying HBO₂ therapy for the treatment and prevention of ARDS, sepsis and multiple organ failure.

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