to avoid the negative consequences of decreased oncotic pressure.

The delivery of free water along with albumin will contribute to the mobilization of the large amounts of sodium that have accumulated in the interstitial and extra-cellular spaces during the first 24 hours. By day 3, the interstitial fluids that have accumulated during the first 24–48 hours must be mobilized and excreted. This generally required an active stimulation of diuresis using loop diuretics (generally furosemide) in combination with an aldosterone antagonist aldactone. Calculated fluid balances are by definition wrong, as they do not take into account the exudative losses through the burn wounds (about 0.5–1L/10% TBSA/day). The condition may be complicated by the used of fluidized or air beds, which cause an even greater loss of free water.

Other organ function/dysfunction and support

The nervous system

Brain, pain, analgesia and sedation

Neurological disturbances are commonly observed in burned patients. The possibility of cerebral edema and raised intracranial pressure must be considered during the early fluid resuscitation phase, especially in the case of associated brain injury or high voltage electrical injury. Several patho-physiological mechanisms are involved [10] including cerebral glucose metabolism alterations as shown in animal models [25, 108]. Inhalation of neurotoxic chemicals, of carbon monoxide, or hypoxic encephalopathy may adversely affect the central nervous system as well as arterial hypertension [10]. Other factors include hypo/ hyper-natremia, hypovolemic shock, sepsis, antibiotic over-dosage (e. g., penicillin), and possible over-sed- ation or withdrawal effects of sedative drugs.

Pain and anxiety will generally require rather large doses of opioids and sedatives (benzodiazepines mainly). Continuous infusion regimens will generally be successful in maintaining pain within acceptable ranges. Sedatives and analgesics should be targeted to appropriate sedation and pain scales. Thus prevent-

ing the sequelae associated with over-sedation and opioid creep; namely fluid creep and affects on the central and peripheral cardiovascular system [96, 105]. Therefore, consideration should be given to the use of NMDA receptor antagonist, such as ketamine or gabapentine, who have important opioid sparing effects to decrease the need for opioids and benzodiazepines [85]. We find multi-modal pain management combining a long acting opioid for background pain, a short acting opioid for procedures, an anxiolytic, an NSAID, acetminophen, and gabapentin for neuropathic pain control [85] used at our institution targeted to SAS (sedation score) and VAS (visual analog scale) scores provide adequate analgesia and sedation.

Intensive care unit-acquired weakness

While survival and main organ function (i. e. CNS) appears to be the focus in the intensive care units; we must not forget about long-term outcomes and specifically the peripheral nervous system and muscular system. Hence there needs to be discussion of one of the more important sequelae of critical illness: neuromyopathy.

The importance of positioning and prevention of peripheral nerve compression is well known and ingrained in the daily practices of most critical care units. In this section we will briefly discuss the risk factors for ICU acquired weakness and modalities for its prevention. The main risk factors include: multiple organ failure, muscular inactivity, hyperglycemia, use of corticosteroids and neuromuscular blockers. A recent publication by de Jonghe et al. [31] revealed that early identification and treatment of conditions leading to multiple organ failure, especially sepsis and septic shock; avoiding deep sedation and excessive hyperglycemia; as well cautious corticosteroid use; and promoting early mobilization might reduce the incidence and severity of ICU acquired weakness.

Respiratory system and inhalation injury

The discussion of multiple modes of ventilation is beyond the scope of this section, for more extensive details on the topic please see the chapter on ventilation. In this section we do need to discuss the various modalities available for VAP (ventilation associated

pneumonia) prevention, treatment of inhalation injury and ARDS.

Ventilator associated pneumonia

The ABA guidelines for prevention, diagnosis, and treatment of ventilator-associated pneumonia (VAP) in burn patients were published in 2009 [69]. The guidelines are as follows:

Mechanically ventilated burn patients are at high risk for developing VAP, with the presence of inhalation injury as a unique risk factor in this patient group.

VAP prevention strategies should be used in mechanically ventilated burn patients.

Clinical diagnosis of VAP can be challenging in mechanically ventilated burn patients where systemic inflammation and acute lung injury are prevalent. Therefore, a quantitative strategy, when available, is the preferable method to confirm the diagnosis of VAP.

An 8-day course of targeted antibiotic therapy is generally sufficient to treat VAP; however, resistant Staphylococcus aureus and Gram-negative bacilli may require longer treatment duration.

Any effort should be made to reduce length of intubation

Inhalation injury

Inhalation injury is a significant confounder in burn injury increasing morbidity and mortality. There remains some controversy in the mode of ventilation used, however, we still need to establish diagnosis methodology and treatment modalities. The diagnosis ranges from history and physical findings, to bronchoscopic examination and serum marker measurements. Despite this variety there can be agreement that thermal injury associated with being in an enclosed space, loss of consciousness, and severe head and neck burns can have associated inhalation injury. The grading can be established by bronchoscopy but its relationship to possible mortality, length of ventilatory requirement, and need for tracheostomy remains unclear.

Asphyxiating gases such as carbon monoxide (CO), and cyanide (CN) are frequently associated with inhalation injury. The treatment for CO toxicity

remains normobaric 100% O2. The role of hyperbaric oxygen remains controversial, although both physiological data and some randomized-trial data suggest a potential benefit, in particular in terms of reduction of cognitive sequelae: it has been included in the guidelines of the Undersea and Hyperbaric Medical Society [57, 104].

Cyanide toxicity associated with inhalation injury can be as result of burning of many household products, and it remains a diagnostic difficulty, as markers such as elevated blood lactate, elevated base deficit or metabolic acidosis used as evidence for cyanide poisoning in smoke or burn victims also represent under-resuscitation, coexisting traumatic injury, carbon monoxide poisoning or exposure to an oxygen-deficient atmosphere. Regardless, aggressive resuscitation and administration of 100% oxygen is indicated. The need for specific antidotes in cyanide poisoning is considered controversial in the U. S. [9, 19, 35], while it is widely accepted in Europe: intravenous hydroxocobalamine has become standard pre-hospital management in case of suspicion of cyanide poisoning [67] due to its improved safety profile for children and pregnant women [57, 90]. Aggressive supportive therapy aimed at the restoration of cardiovascular function augments the hepatic clearance of cyanide without specific antidotes and should be the first line of treatment. The role of cyanide poisoning in human smoke inhalation injury is undetermined, and lacks evidence.

Among other treatment modalities for inhalation injury b2-agonist, nebulized heparin and NO but have not yet proven superiority. In an animal model treatment of inhalation injury with a b2-agonist, albuterol, resulted in improved lung physiology by reducing pulmonary edema and lung vascular permeability to protein [73]. Although, these results are promising there’s lack of evidence for its use in humans.

Inhalation injury results in airway obstructive casts, which are composed of mucus secretions, denuded airway epithelial cells, inflammatory cells, and fibrin [30]. The presence of fibrin solidifies the airway content forming the firm cast that is hard to remove by single cough or even by aggressive airway toilet. Therefore, prevention and/or dissolution of airway fibrin deposition is crucial in effective airway management. Nebulized heparin therapy has been

demonstrated in animal and single-center studies to have potential efficacy in inhalation injury, particularly when combined with other anti-inflammatory agents and antithrombin [101].

Inhaled nitric oxide (NO) has been used as a therapeutic agent in pulmonary hypertension and to decrease intrapulmonary shunt [86]. Inhaled NO has been studied in animal models which have consistently shown reduction in pulmonary hypertension associated with inhalation injury, and variable reduction in shunting [91]. The studies in humans are small and limited, but invariably have shown improvement of PaO2/FiO2 ratio. There is no advantage in dosage above 20ppm. Given the current status of information available, the use of inhaled NO for inhalation injury should be restricted to patients that have failed conventional strategies with persistent refractory hypoxemia and PaO2/FiO2 ratios > 80 [91].

Renal failure and renal replacement therapy

Acute renal failure (ARF) is a major complication of burn injury. The incidence of ARF in burned patients has been reported to range from 1.2 to 20% and the incidence of ARF requiring renal replacement therapy (RRT) from 0.7 to 14.6% [70]. Although ARF is relatively rare, early diagnosis is important, as the mortality of burn patients with ARF has been reported from 50–100% [27, 44]. Applying the RIFLE classification to burn patients, Coca et al. found that the incidence of acute kidney injury was 27%, and it carried with it a mortality rate of 73% in the patients with the most severe acute kidney injury (requiring dialysis). Burn-related ARF can be divided into early and late ARF, depending on the time of onset with each having different etiologies [44]. Early ARF occurs during the first 5 days post-burn and its main causes are hypo-volemia, hypotonia and myoglobinuria. Prevention focuses on early aggressive fluid resuscitation and escharotomies or fasciotomies. Late ARF begins more than 5 days post-burn and is usually multi-factorial (generally caused by sepsis and/or nephrotoxic antibiotics) [44]. Regardless of the cause, there is mounting evidence that renal replacement therapy (RRT) should be instituted as early as possible in burn patients with renal dysfunction before the traditional criteria for RRT has been

established [28]. Further to the discussion of RRT, is the choice in mode of delivery. CRRT (continuous renal replacement therapy) offers several potential advantages in the management of severe acute renal failure in burn patients. It is slow and continuous, consequently allowing for very efficient metabolic clearance and ultra-filtration of fluids, while minimizing hemodynamic compromise. Thus allowing for ongoing optimization of fluid and metabolic management [39]. There needs to be further studies to establish the triggers for instituting RRT in the burn patient with renal dysfunction followed by appropriate choice of modality (intermittent vs. continuous), dose and duration of therapy.

Gastro-intestinal system

GI complications/GI prophylaxis/enteral nutrition

The affect of thermal injury on the gastro-intestinal system was identified in 1970 with the description of Curling’s ulcer [79]. Alterations in distribution of blood flow occur in the early post-burn period and are due to neurogenic and humoral release of catecholamines and prostanoids. During the initial hours, splanchnic blood flow is reduced, except for flow to the adrenals and to the liver. TXA2 is likely to play a major role in gut dysfunction, promoting mesenteric vasoconstriction and decreasing gut blood flow. Poorly perfused organs shift towards anaerobic metabolism leading to acidosis. Aggressive fluid resuscitation restores perfusion to a great extent. But with over-enthusiastic fluid delivery, increasing intra-abdominal pressures and consequently abdominal compartment syndrome (ACS) becomes a matter of concern in both adult and pediatric burn patients [51, 71]. The Ivy index (250 ml/kg fluid resuscitation) is a cut-off value beyond which trouble is nearly certain. Abdominal pressures start rising, soon reaching the “gray zone” of 15–20 mmHg, and then the danger zone > 20 mmHg, beyond which medical measures must be taken to reduce the IAP to avoid splanchnic organ ischemia. Figure 1 shows an example of progressive increase of intra-abdom- inal pressures associated with excessive fluid resuscitation in a young man with 95% TBSA burn resulting in a near arrest. Laparotomy is an extreme

Fig. 1. Development of intra-abdominal hypertension (magenta bars) with pressure 37 mmHg 12 hours after injury in a young man burned 95% TBSA who had received 26.1 L of fluid resuscitation by that time (350 ml/kg in 12hrs). As a consequence several organ failures occur: cardiovascular (shock), respiratory (oxygenation) and renal (anuria) despite heavy vasopressor (norepinephrine) and inotropic (dobutamine) support

treatment tool, that indicates failure of medical management, or the combined presence of severe 3rd degree burns to the trunk and fluid resuscitation. IAP monitoring is essential for TBSA > 30%.

Early enteral feeding should be initiated no later than 12 hours after injury. The benefits of this strategy are numerous: increasing blood flow to the splanchnic compartment before edema makes it impossible, maintaining pyloric function [84], maintaining intestinal motility, and reducing significantly infectious complications [63].

Indeed the gastrointestinal function, including the pyloric function, is depressed immediately after thermal injury. A true paralytic ileus will ensue for many days if the gastrointestinal tract is not used [84]. Opiates and sedatives, further depress the gastrointestinal function. Stress ulcer prophylaxis is mandatory (e. g. sucralfate, ranitidine or proton pump inhibitors), since the bleeding risk is elevated in burn injuries and may be life-threatening [79].

Due to the large doses of opioids and sedatives used during the early phase of treatment, constipation is frequent and may become critical with the development of ileus and intestinal obstruction by feces. Prevention should be initiated from admission using fiber containing enteral diets, lactulose

(osmotic cathartic), and enemas when the other measures have failed.

Gut complications may be life threatening: in addition to the already mentioned ACS and constipation, the patients may develop Ogilvie syndrome, ischemic and non-ischemic bowel necrosis, and intestinal hemorrhage. A careful tight supervision of bowel function with daily examinations is therefore mandatory, particularly in perioperative periods with intra-operative hemorrhage leading to hypovolemia, which exposes the patient to gut hypo-perfusion and their threatened complications.

Hepatic dysfunction

Severe burn injury causes numerous metabolic alterations, including hyper-glycemia, lipolysis, and protein catabolism [4]. These changes can induce multi-organ failure and sepsis leading to significant morbidity and mortality [21, 74]. Liver plays a significant role in mediating survival and recovery of burn patients, and preexisting liver disease is directly associated with adverse clinical outcomes following burn injury [53, 78, 102]. In the study by Price et al., they demonstrated that preexisting liver disease increased mortality risk from 6 % to 27 %, indicating that liver impairment worsens the prognosis in patients with thermal injury. Severe burn also directly induces hepatic dysfunction and damage, delaying recovery. More recently the work by Jeschke et al. [56] and Song et al. [93] has shed some light on the mechanism of the hepatic dysfunction following thermal injury, mainly by the up-regula- tion of the ER stress response, and increased cell death contributing to compromised hepatic function post-burn. Thus, one must not only be cognizant of the significant deleterious affects of hepatic dysfunction in the thermally injured patient as it has significant consequence in terms of multi-or- gan failure, morbidity and subsequent mortality of these patients; one can focus therapeutic modalities to alter this response and possibly improve outcome.