Negative Prognostic Factors in Severe Burns – Implication for Clinical Outcome

Introduction: Severe burn injuries still are a major challenge for the entire healthcare system. Multiple predictive factors may influence the prognosis of burn patients and a careful management of those parameters will decrease the morbidity and mortality and will determine an improvement in patient’s fi nal functional outcome. Material and Methods: We present a two years study on the burn patients hospitalized in our institution. A total of 355 burned patients were hospitalized during this period, 210 (59%) of them being addmited in Critical Care Burn Unit. A detailed analysis was performed on those 210 critical patients in order to determine the parameters that aggravate the prognosis of burn injuries. A large data panel was taken into consideration regarding burn severity, mechanism of injury, patient characteristics, associated illnesses, promptitude in hospitalizing the patient in our burn center; ABSI score was used to evaluate the mortality risk, burn injury-associated complications were noted and analyzed. Results and discussion: We highlighted a series of parameters regarding therapeutic management that influence the outcome of the patient after severe burn injury: an adequate hydro-electrolytic resuscitation in the acute phase, further support of vital functions, early excision and grafting of deep burn injuries, comorbidities treatment and adherence to rehabilitation and follow-up program. ABSI Score is an important tool in the assessment of mortality in burn patients. Multiple complications were encountered in our patients: infections, pulmonary, cardiac, renal, thrombo-embolic, hematologic, digestive and neurologic disorders. Conclusion: A detailed analysis of the physiopathology of burn injuries and their complications is essential for providing an adequate prompt treatment for decreasing morbidity and mortality. Mortality still represents the primary outcome evaluation for burn care, therefore scoring systems aim to use the most predictive patient and injury-related parameters to appreciate an expected mortality for a given patient. Early excision of the devitalized tissue and subsequent grafting reduce the local and systemic effects of the mediators released from the burned tissue with cessation of the progressive inflammatory chain. Early recognition and treatment of burns complications, especially severe infections represent an important prevention strategy, improving survival after these severe injuries.


INTRODUCTION
Burn injuries are a major public health problem all over the world and despite signifi cant improvements in critical care and surgical treatment, major burns are associated with high morbidity and mortality and poor recovery outcome. Patients with severe burns need immediate intervention and rapid initiation of specialized treatment in a dedicated critical care burn unit in order to minimize morbidity and mortality. Th e complex nature of burn injuries requires an integrative approach, by a multidisciplinary team in order to obtain an optimal care.
Multiple factors may infl uence the prognosis of burn patient's therefore an appropriate identifi cation and a careful management of those parameters will decrease the morbidity and mortality and will determine an improvement in patient's fi nal functional outcome.
is an accurate evaluation of the severity of the trauma, estimation of the prognosis for the patient, allowing a stratifi cation of patients that guide therapeutic strategies 6,8 . A prognostic score that has proven useful over the years for mortality prediction is the Abbreviated Burn Severity Index (ABSI score), introduced by Tobiasen et al. in 1982 6,10 . Th erapeutic measurments correctly applied to burn patients are a major determinant of the fi nal outcome. Severe burn treatment is very complex and it is mandatory to be adapted to the dynamic physiopathological changes observed after combustional lesions.
Th ree major phases are described in the evolution of burn injuries, each one with specifi c therapeutic management ( Table 2): It is very important to rapidly identify the complications, especially infections, and apply the specifi c therapeutic measures throughout the patient course during these phases. Th e current recommendations are to avoid the development of organ dysfunction and to ensure adequate support to elude conditions that favor its onset. Early excision of the burn eschar and wound grafting, rapid mobilization of the patient and prompt identifi cation and treatment of any systemic disorder determine the achievement of this goal 1 .

MATERIAL AND METHOD
We investigated a total number of 355 burned patients hospitalized in Bucharest Clinical Emergency Hospital for 2 years, between 01.05. 2016-01.05.2018, 210 (59%) of them being addmited in Critical Care Burn Unit.
A detailed analysis was performed on those 210 critical patients in order to determine the parameters that aggravate the prognosis of burn injuries. A large panel of data was taken into consideration regarding burn severity, mechanism of injury, patient characteristics, associated illnesses, promptitude in hospitalizing the patient in the burn center; ABSI score was used to evaluate the mortality risk, burn injury-associated complications were noted and analyzed. A statistical study was performed in order to determine the correlation between ABSI burn prognostic score and the observed mortality.
ABSI Score was calculated after Tobiasen scheme as we can see in Table 3.

RESULTS
We evaluated the mortality of all admitted patients in our unit and we noticed a total mortality of 36.6%, as seen in Graphic 1 with a mortality of 60.4% of patients admitted on Critical Care Burn Unit, as seen in Graphic 2.

PHASE DURATION GOALS EMERGENT
From the moment of injury until the complete fluid resuscitation (the fi rst 72 hours)  In Graphic 4 we present the distribution of our critical patients' age groups and we can see a maximum number of patients in the group between 41 and 60 We traced the moment of death in our patients and we noticed a total of 20 deaths in the fi rst 72 hours, which is the emergent phase, as seen in Graphic 3.
Patient characteristics were evaluated in our study group. Th e distribution of home environment in pati-  Th e burn depth was analyzed for its infl uence for burn severity and as we can see in Graphic 6, there were 72% of patients having a third degree burn.
Taking into account the mechanism of injury as one of the negative prognostic factors in our study we encountered a number of 73 explosions (34% of patients), 7% electrocutions and 2% chemical burns, as seen in Graphic 7. In 23 patients there were work-related burns (11% of patients).
years old (76 patients) and a large elderly group, after 61 years old (81 patients).
Regarding the extent of burn lesions in our group, Graphic 5 is showing 63.3% of patients with ≥30% burned TBSA.    correlation between the ABSI score and mortality is illustrated in the study group with a very high correlation (r=0.9310) and with high statistical signifi cance (p<0.001, confi dence of 99.9%) between the ABSI score and the observed mortality; a very high correlation (r=0.9539) with statistical signifi cance (p<0.0075, confi dence of 99%) between the ABSI score and the estimated mortality is also seen.
We looked at the modality of hospital admission and we observed a large number of transferred patients from other centers-60%, 40% being direct admissions (Graphic 11). Th ere were 126 patients transferred from other centers: 82 (65%) of patients were transferred during the fi rst day of the injury and 44 (35%) of patients after 24 hours.
During hospitalization in our Critical Care Burn Unit, 133 patients (63.3%) developed systemic com-We followed the presence of inhalation injury in our patients and determined 66% aff ected patients as we can see in Graphic 8.
We noticed that 156 patients from 210 (74.3%) required intubation and mechanical ventilation, with an average of 267 hours of mechanical ventilation/patient with a median of 185 hours/patient (Graphic 9). A total of 22 tracheostomies were performed by our ENT surgeons.
Th e association of concomitant injuries aggravates the prognosis of the burn patients and we can notice in our study the presence of costal and limb fractures, pneumothorax, aspiration pneumonia, cranio-cerebral trauma and intra-abdominal hemorrhage, as seen in Table 4.
ABSI score was calculated in our study for asses its role in mortality prediction. In the Graphic 10, the cases of Escherichia coli, 18 cases of Pseudomonas aeruginosa (Graphic 14).
Th e screening on day 14, the study group is smaller due to the occurred deaths, but we noticed 18 cases of coagulase negative Staphylococcus, 23 cases of Acinetobacter, 18 cases of Klebsiella, 2 cases of Escherichia coli, 18 cases of Pseudomonas aeruginosa (Graphic 15). plications (Graphic 12) and 10 of those patients required renal substitution therapy. Other complications as ophthalmological, psychiatric and dermatological were also seen in a smaller amount of cases.
Infectious complications were assessed separately in our study. In Graphics 13-16 we notice the fl uctuation of microbial distribution in our patients at admission, day 7, day 14 and day 21, as we wanted to note sequentially the microbial distribution map in our burned patients, in order to evaluate and determine the infectious pattern during the evolution phases of burn injury.
Th e screening on admission noticed the expected saprophyte fl ora (126 cases of coagulase negative Staphylococcus, 62 cases of Staphylococcus aureus and 13 cases of diff erent types of Streptococcus), but also 36 cases of Acinetobacter, 49 cases of Enterococcus, 27 cases of Escherichia coli, 27 cases of Pseudomonas aeruginosa, that in many cases are associated with antibiotic resistance (Graphic 13).
Th e screening on day 7 noticed a decrease of the expected saprophyte fl ora (29 cases of coagulase negative Staphylococcus, 9 cases of Staphylococcus aureus), but also 52 cases of Acinetobacter, 33 cases of Klebsiella, 6 Th is rural-urban diff erence is also valid in our geographic region, with patients coming from rural areas attending later the territorial medical service and consequently presenting a delay in the admission to the burn unit.
Th e gender distribution in our group was approximately 2:1, favoring for male patients. As regarding age group distribution, 36.2% of our patients were between 41-60 years. We noticed a large group of elderly patients over 61 years (38.6%).
In a large study published by Li et al. on 6325 pediatric and adult burn patients, the gender analysis show a male patients predominance(male-to-female ratio was 2:1); in the adult study group the main aff ected age decade being 41-60 years (26.2%) 16 .
Older patients are the most vulnerable to the morbidity and mortality associated with burn injuries, therefore preventive strategies should be developed and promoted in elderly population group 17 . Lionelli et al. attested age as a signifi cant variable for mortality prediction, in their study (independent of TBSA and inhalation injury-holding constant those two parameters), they found that the mortality risk was multiplied by a factor of 1.1 for each additional year in patient's age 18 .
A study conducted by Lundgren et al. demonstrated that the age of patients, independent of existing comorbidities, along with inhalation injury and TBSA involved are the most signifi cant parameters that determine the mortality risk during hospitalization after burn injury 19 .
We had a large proportion of extensive burns: 63.3% over 30% TBSA, 50% of our patients having more than 40% TBSA, suggesting a poor prognostic.
Morbidity and mortality risk depends on TBSA, increasing in a linear manner: the more extensive is the burn, the higher is the risk. Jeschke et al. established a critical threshold for morbidity and mortality after burn injuries at 40% TBSA burned for adult patients and 60% TBSA burned in pediatric patients, showing that patients with burns at or exceeding these cutoff values are at high risk for severe complications and death, even if they are treated in highly specialized burn centers. Th e same study has also taken into account the age of the patients and set a lower survival cutoff at around 30% TBSA for elderly patients 20 .
Th e burn depth, with presence of third degree burn is part of the factors that infl uence burn severity and in our group we encountered a large proportion of patients (72%) with full thickness burns. Th ese cases Th e screening on day 21 revealed 11 cases of coagulase negative Staphylococcus, 16 cases of Acinetobacter, 15 cases of Klebsiella, 2 cases of Escherichia coli, 9 cases of Pseudomonas aeruginosa (Graphic 16).

DISCUSSION
Major burns are a serious problem for our national health system as for other developing countries and even for states with a high standard of care. Each year, in United States 500000 patients visit the emergency departments for burn injuries, from these around 40000 patients present severe burn injuries requiring hospitalization with 4000 deaths per year. Severe burn injuries lead to severe systemic alterations being associated with high risk of morbidity and mortality [1][2][3] .
Trough this paper we tried to identify the large panel of factors that may infl uence the prognostic of patients with severe burn injuries with the aim to improve and standardize our practice in order to reduce the complications, decrease the morbidity and mortality rates for better fi nal outcome of those problematic patients. Patient-related and injury-related characteristics were analyzed and also particularities encountered in our center were noted.
Demographical characteristics (the residence environment, gender, age) of the patient are taken into consideration in relationship with burn injury prognosis.
We noticed a slight predominance of rural-provenance patients in the case of hospitalizations in our Critical Care Burn Unit.
In France, Vidal-Trecan et al. identifi ed higher severity of burns from rural areas: there are usually produced outdoor, due to fl ames, explosions or open fi re; in these report rural burns were more extensive, involving a larger TBSA, deeper and determined more deaths than urban burns 13 . In a Turkish study performed by Tarim MA., burns produced in rural areas were also deeper, larger, and causing more deaths than those from urban areas, probably due to the particularities of the rural population, including the delay of transportation to the burn units 14 . Mian et al. published a study on urbanrural dichotomy of burn patients from United States (data from Georgia and South Carolina) and highlight the socioeconomic disparities between the urban and rural population, with young urban population groups that live in poor socioeconomic status communities being at the higher risk. For the rural areas the access to medical facilities is more diffi cult and also the burn unit referral is delayed 15 . space, the presence of carbonaceous sputum, changes in voice, stridor, wheezing 25,29,30 .
Nowadays, the standard for diagnosis of inhalation injury in most major burn centers is fi ber-optic bronchoscopy. Th e limitation of this investigation is the impossibility to evaluate the distal airways 31 . Th ere has been found a correlation between the severity of inhalation injury assessed with fi ber-optic bronchoscopy and mortality 32  Th ere is no ideal strategy for the patients with inhalation injuries and the management consists of supportive care 34 .
It has been reported the benefi t of noninvasive ventilation, but the best moment to use it in the burn injured patients is unclear 35,36 .
Studies have shown that tracheostomy is safe in burn patients, but there is no consensus when it is the best time to do it. Patients with major burns and with severe inhalation injury are those who can benefi t from an early tracheostomy, because they need numerous surgical procedures and longtime ventilation 37 . Tracheostomy eases ventilator weaning by reducing dead space, airway resistance, work of breathing and the need for sedation 38 . With tracheotomy there is a shorter and a more direct airway access, the cough eff orts and suctioning are likely to be more eff ective, patient comfort is improved, with earlier ability to speak. Overall tracheostomy seems to associate with lower risk of ventilator-associated pneumonia, lower mortality and shorter hospitalization and staying in intensive care unit in comparison with orotracheal intubation 39 .
An interesting study from United States was published by Kagan et.al.based on analysis of patients included in DRG (diagnosis related group) 504 Classifi cation-burned patients with extensive injuries requiring skin grafts along with f patients with non-extensive third degree burns with skin grafts who need >96 hours (4 days) of mechanical ventilation: patients from this category who required ≥96 hours of mechanical ventilation had around 10 times more the number of ventilator and intensive care unit hospitalization days in comparison with patients with extensive burns but with <4 days mechanical ventilation. Th ese patients had also doubled length of hospitalization and cost than patients with <96 hours of mechanical ventilation 40 .
require surgical treatment in order to improve their prognosis.
Th e standard of care is represented by the early excision and grafting of the full thickness burn wounds: early excision decrease infections risk, length of hospital stay and mortality (mortality is decrease when burns are not associated with inhalation injury); burn eschar excision is associated with increased need of blood transfusion 21,22 .
If possible, the excised burn wound is covered with a split-thickness autograft, which can be meshed with diff erent expansion rate to increase its surface. Patients presenting extensive deep burns don't have suffi cient available donor sites for autografting and they need temporary or permanent coverage with skin substitutes: temporary coverage with human allografts, xenografts, synthetic or biosynthetic products or defi nitive coverage with compounds like cultured epidermal autografts, dermal substitutes(Integra, Alloderm, Matriderm) or bi-layered products (Apligraf ) 21,23,24 .
Regarding burns etiology, in our group 85% were fl ame injuries and in 34% of cases explosion was the cause. Th is distribution of predominant mechanism usually associates with severe burns of functional areashead and upper extremities and also with airway burns, a major negative prognostic factor. Two-thirds of our patients in the Critical Care Burn Unit presented inhalation injuries and three quarters of the 210 critical patients required intubation and mechanical ventilation. Airway burns are evaluated in our center using the fi ber-optic bronchoscope.
Inhalation injuries in burn patients are still associated with an important morbidity and mortality rate 25 . Th e inhalation injury is noted to be an independent factor for mortality prediction in burn patients and worsens survival even among patients of same age and burn size 26 . Th e infl ammatory response in the case of inhalation injuries requires increased fl uid resuscitation volumes compared to burn patients alone, determines progressive pulmonary dysfunction, requires more ventilation days, increases the risk of pneumonia, and acute respiratory distress syndrome (ARDS) 25,27 . Th e retrospective study made by Swanson et al. (n = 5975 patients) during a 12-year period showed that inhalation injuries in burn patients are the second most common cause of death in the fi rst week (16%) after the burn injury, the fi rst cause being the burn shock (62%) 28 .
Th e clinical diagnosis of inhalation injuries is subjective: includes the existence of facial burns, singed nasal vibrissae, a history of exposure to smoke in a closed good liquid resuscitation is the evaluation of diuresis: 0.5 ml/kgc/h. During the acute phase it is important to also evaluate the color of the urine (dark urine is a sign of myoglobinuria that may appear in massive burns or electrical burns)-if the color is dark, it is a high suspicion of kidney failure, requiring aggressive and prompt treatment 1 . Th is fi rst phase, described as the ebb phase lasts the 48-72 hours of thermal injury with patients presenting oxygen consumption, decreased cardiac output and metabolic rate and are both glucose intolerant and hyperglycemic 42 . Th e primary goal after the acute phase is to restore and preserve tissue perfusion and prevent ischemia produced by post-combustion shock with hypovolemic and cellular disorders 43 .
After the acute, resuscitative phase, starts the fl ow or hypermetabolic phase. Severe burns determine a response that involves almost all biological systems. Systemic infl ammation, hypermetabolic status with muscle wasting and resistance to insulin are hallmarks of the physio pathological response to major burns, which determine metabolic changes persisting for several years following burn injury 43 . During these phase multiple disorders may appear at diff erent levels: cardiovascular, renal, pulmonary, neurological, gastrointestinal, hepatic, metabolic and immunologic 43 .
A large proportion of our patients developed systemic complications, more frequently aff ecting respiratory and cardio-circulatory systems, followed by metabolic, renal and hematological complications. Th ose situations require a specifi c supportive therapeutic management involving a multidisciplinary care-giving team, but in very diffi cult cases a poor outcome was encountered, despite intensive supportive therapy, patients developing multisystem organ failure with consecutive death for many of them.
Infections are the most sever and the most frequent complication and requires adequate diagnosis and treatment. We perform microbiological screening: testing at admission and once a week or in case of clinical signs from all potential sites. Th e antibiotherapy is administered according to antibiograms, but if needed, when clinical and paraclinical signs are suggestive for infection, the antibiotherapy is started empirical, with broad spectrum and immediately after the antibiogram is available, targeted antibiotic is introduced. De-escalation principle is applied, in order to administer the drug eff ective on our germs but with a narrow spectrum and if possible to avoid the reserve antibiotics.
Natural protective barriers (skin, respiratory and digestive tract) are usually aff ected in severe burns, along As we see, a prolonged period of mechanical ventilation transposes in a poor prognosis for the patient and high consumption of material resources, therefore this indicator (number of hours of mechanical ventilation) has to be analyzed more carefully in order to early diagnose and treat specifi c complications for improve patient outcome and also to develop an economic strategy for an adequate fi nancial resource distribution to burn centers. Th is situation applies also in our case, due to long termed required mechanical ventilation in our patients (an average of 11.12 days of mechanical ventilation in our critical patients).
In a study published by Forster on 2813 patients with the aim to analyze the predictive value of ABSI score, it was seen that each of the variables of ABSI score is a signifi cant predictor of mortality. Also they compared the estimated mortality of the patients using the ABSI score with the calculated mortality in the analyzed group and they validated the accuracy of the ABSI score in predicting burn patient's mortality, attesting this scientifi c value of the ABSI since more than 35 years from its introduction by Tobiasen et al. 10,41 .
We noticed similar results in our study: according to statistical signifi cant data, ABSI score is a very important tool for prediction of mortality in our patients. We had high mortality levels, but those data were expected when we analyzed the prognostic scores, due to severity of each parameter encountered in our group of patients.
A particular situation encountered in our burn unit was a high proportion of patients transferred from other centers around the country, often for long distances reaching 600 km, requiring diff erent transport modalities (air transport by plane or helicopter and ambulance). Many of those patients were transferred after the fi rst day from the moment of burn occurrence and we noticed the risk associated with these situations: inappropriate initial resuscitation, transport-related risk and an increased chance of infectious complications (in regional hospitals it is diffi cult to assess the appropriate isolation conditions that are mandatory for the burn patients). Th e ideal situation is the admission of the severely burned patient in a burn unit in the fi rst 8 hour from injury occurrence.
It is essential for the burn patient to begin the liquid resuscitation right away and according to the Parkland formula: 4 ml crystalloid solution x kg x total burn area = ml for the fi rst 24 hours, of which half will be given within the fi rst 8 hours of injury (not from the moment when the patient is hospitalized), and the rest within the next 16 hours. Th e most adequate indicator for a (rural provenience, elderly patient), injury-related (extens ive and deep burns, mechanism of injury including explosions, electrocutions and chemical burns, presence of inhalation injury, necessity of prolonged intubation and mechanical ventilation) and also infrastructure determinants (insuffi cient established adequate burn centers and delayed transfers to those center after the injury occurrence) has to be taken into account as they determine higher morbidity and mortality rates in severe burned patients. Early excision of the devitalized tissue and subsequent grafting reduce the local and systemic eff ects of the mediators released from burned tissue avoiding the progressive infl ammatory chain. Prompt recognition and treatment of burns complications, especially severe infections represent an important prevention strategy, improving survival after these severe injuries.

Compliance with ethics requirements:
Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.
with activation of pro-infl ammatory cascade getting to a complex immune system disorder, cumulating both cellular and humoral responses to infection; those immunologic alterations determine, in this context infectious complications that are a rule in severe burn evolution marked usually by the presence of opportunistic germs. Th e most important strategy is the prevention of infectious complications.
According to the evaluated data from our study, we can observe that mortality and substantial morbidities occur and lead to severe debilitation of major burned patients, imposing a continuous adjustment of evaluation and treatment protocols in an adequate infrastructure with sustainable resources.

CONCLUSIONS
A clear understanding of the physiopathology of burn injuries and their complications is essential for providing an adequate treatment to reduce morbidity and mortality. Mortality still represents the primary outcome measure for burn care, therefore scoring systems aim to use the most predictive patient and injury-related factors to yield an expected mortality for a given patient. ABSI score is a signifi cant predictor of mortality, validated also in our study group. Presence of a series of a negative prognostic factors: patient related