The appropriate resuscitation strategy given such conflicting data remains elusive. Some have recommended resuscitation with colloid when administered fluid volumes surpass a threshold, e. g., when requirements reach 120% of predicted or 6 cc/kg/hr [36, 40, 41]. Resuscitation with colloid has been linked with a lower incidence of intra-abdominal hypertension in burn patients [40], and has been demonstrated safe with the exception of administration to head trauma patients [42].

Pharmacologic research has unveiled possible drug therapies to support oxygen delivery to the tissues and maintain organ perfusion, in place of high volumes of fluid. For example, administration of high doses of ascorbic acid, an antioxidant, is associated with decreased ventilator dependence, as well as lower fluid requirements during clinical resuscitation [43].

Until further studies validate new therapies, organ support during burn resuscitation remains an art as well as a science for the practitioner. Resuscitation formulas serve as guidelines, and intensivists should titrate crystalloid infusions to blood pressure and urine output, using base deficit and invasive hemodynamic monitoring as supplemental guides in difficult cases. Physicians should perform serial physical examinations and monitor bladder pressures to detect early complications from volume overload, and consider colloid fluid replacement in the event of overresuscitation.

Post-burn hypermetabolism

After the acute resuscitation phase, burn patients enter a hyperdynamic state that persists for months. A continued catecholamine and cytokine surge increases the resting metabolic rate by 160–200%, and induces prolonged tachycardia, fever, muscle protein catabolism, and derangement in hepatic protein synthesis [44–48]. These changes further threaten patients’ organ function, and with increased risks of infection and impaired wound healing, as well as cardiomyopathy.

Primary management of post-burn hypermetabolism is early excision of full-thickness burns, which attenuates the hypercatabolic state [47]. Beta blocker therapy has also demonstrated several beneficial ef-

fects in burn patients. Beta blockers decrease heart rate and cardiac oxygen demand, thus protecting against cardiomyopathy. Additionally, studies demonstrate that beta blocker therapy – in particular, propranolol – decreases resting oxygen expenditure, attenuates muscle catabolism and lypolysis, and modifies catecholamine-mediated defects in lymphocyte activation [49, 50]. Therapy with the testosterone analog oxandrolone also has beneficial effects, as it significantly decreases the rate of weight and nitrogen loss among burn patietns, and facilitates donor site healing compared with placebo [51–53].

Individual organ systems

Central nervous system

After severe burn injury, patients often require intubation and mechanical ventilation, to support their lungs in the settings of inhalation injury and large volume shifts. Pain and stimulation from the endotracheal tube require that patients receive sedation while intubated, potentially at high doses. Given potential effects of the post-burn inflammatory response on the central nervous system, physicians should consider regular interruptions of sedation to obtain a neurologic exam from their patients. Following severe burns, phagocytes can cross the bloodbrain barrier, where they release reactive oxygen and nitrogen species, proteases, cytokines, and complement proteins into the brain [54]. These inflammatory molecules can damage resident neurons and trigger life-threatening cerebral edema, only exacerbated by large volumes of crystalloid infused during resuscitation. It is therefore key for burn surgeons to frequently perform a neurologic exam in their acutely burned patients, to detect deficits early.

The utility of sedation interruption is multifold. In addition to allowing physicians to monitor patients’ neurologic exam, daily interruption of sedation minimizes time on the ventilator and reduces ICU length of stay. In a randomized trial of 336 patients over a 3 year period, patients who underwent sedation interruption required less total benzodiazepines, had a shorter duration of coma, and were 32% less likely to die during the following year than

controls [55]. Daily interruption of sedation should be considered in intubated burn patients.

Carbon monoxide poisoning, common among burn patients with smoke inhalation, delivers particular threat to brain function. Human hemoglobin has an affinity for carbon monoxide 210 times higher than for oxygen. As a result, carbon monoxide displaces oxygen from hemoglobin and induces tissue hypoxia. This hypoxia most severely affects the brain and heart, the organs the highest metabolic demand.

Cerebral hypoxic damage predominates in the cerebral cortex, white matter, and basal ganglia [56]. 84% of exposed patients report headache, and 50% develop weakness, nausea, confusion, and shortness of breath. Progressive hypoxia leads to cerebral edema and increased intracranial pressure, with altered sensorium, seizures, and coma. Initial management is immediate normobaric oxygenation (100%), to reduce the half-life of carboxyhemoglobin from 5 hours to 1 hour. Hyperbaric therapy may be considered in stable patients who display symptoms consistent with carbon monoxide poisoning and who have no contraindications to such treatment if. Six hours of normobaric 100 % oxygen is appropriate treatment in all others. Rarely, patients who recover from acute carbon monoxide poisoning may develop delayed neuropsychiatric deficits, regardless of treatment regimen [56].

Peripheral nervous system

49–77% of patients in the ICU for at least 7 days develop critical illness polyneuropathy, a condition that affects motor and sensory nerve axons and heralds limb weakness and prolonged ventilator weaning [57]. The mechanism, best documented in sepsis, appears driven by proinflammatory cytokines common to the post-burn inflammatory response. Increased microvascular permeability triggers endoneurial edema and extravasation of leukocytes into the endneurial space, with resultant ischemia and axonal degeneration. The result is flaccid and symmetrical limb weakness, as well as reduction of deep tendon reflexes and distal loss of sensitivity to pain, temperature, and vibration. The phrenic and intercostal nerves suffer as well, with prolonged dependence on mechanical ventilation by 2–7 fold [57].

Prevention of critical illness polyneuropathy depends on avoidance of sepsis, multiorgan failure, ARDS, and hyperglycemia, all conditions associated with damage to the axonal microvasculature. The diagnosis can be supported with nerve conduction studies, and early involvement with physical and occupational therapist may be helpful in recovery. 50% of patient with critical illness polyneuropathy fully recover, however clinical improvement can require weeks to months.

Pulmonary

Pulmonary complications after burns occur primarily as thermal or smoke injury to the lungs, or as secondary events, for example, ventilator-associated pneumonia or acute lung injury from activation of the systemic inflammatory response. Smoke inhalation, which follows the inspiration of toxic smoke from the incomplete combustion of synthetic materials [58], affects 10–20% of burn patients and significantly increases the risks of ventilator dependence, increased length of hospitalization, and death [59]. Hot air injures the epithelium of the upper airway, inducing pharyngeal edema and acute airway obstruction in 20–33% of burn patients with inhalation injury [24]. This risk of airway obstruction warrants prompt intubation in any burn patient presenting with a history of carbonaceous sputum, voice change, or dysphagia, or in patients suffering burns within a confined space who have carboxyhemoglobin leves > 10% within one hour after injury [24].

Significant smoke inhalation impairs the function of respiratory cilia, and disrupts epithelial intercellular junctions, with resultant mucosal sloughing. This mucosal injury triggers an inflammatory cascade that compromises the pulmonary microvasculature. The resultant pulmonary edema, leakage of plasma proteins into the interstitium, and formation of alveolar exudates generates fibrin casts within the distal airways, with ultimate bronchial obstruction and constriction [59]. The accumulation of intraand perialveolar fluid compromises gas exchange and pulmonary compliance. When hypoxia progresses to a PaO2/FiO2 ratio of less than 300, this degree of respiratory failure meets criteria for acute lung injury (ALI); when the ratio falls below 200, the patient officially has acute respiratory distress syndrome (ARDS).

ARDS after burn injury is common, with a prevalence as high as 54% among mechanically-ventilated adult patients with major burns [60]. The condition carries a mortality rate of 30–40% [61]. Treatment strategies for ARDS emphasize judicious fluid restriction to minimize pulmonary edema and improve gas exchange, as well as treatment of coincident infections and provision of nutrition. Early eschar excision may truncate the inflammatory response that contributes to ARDS [48]. Additionally, ARDS requires skillful attention to mechanical ventilation. Positive pressure ventilation can further damage compromised pulmonary parenchyma through overdistension and disruption of the alveoli. To avoid ventilator-associated lung injury, intensivists may adopt a lung protective strategy in ARDS, targeting tidal volumes less than 6 mL/kg and end-inspiratory plateau pressures less than 30 cm H2O [58, 62]. Moderate levels of PEEP may help avert recurrent collapse and distension of the alveoli that may worsen lung injury [62]. Data also suggest possible utility in high-frequency oscillatory ventilation for burn patients with ARDS, however this possibility requires further prospective study [63].

In addition to ARDS, ventilator-associated pneumonia (VAP) presents a special problem for severely burned patients. Between 10–20% of burn patients who receive > 48 hours of mechanical ventilation develop VAP, and those with VAP are twice as likely to die as those without [59]. The condition arises secondary to aspiration of secretions from the oropharynx, as well as from the stomach, which gram negative bacteria colonize in critically ill patients. Burn injury and intubation inhibit mucociliary clearance, and loss of the glottic barrier allows for leakage of secretions around the endotracheal tube cuff and into the distal airways. Tactics to avoid VAP include minimization of ventilator time, daily spontaneous breathing trials, chlorhexidine oral rinses to decrease oropharyngeal colonization, and elevation of the head of the bed [58]. Excessive blood transfusion should be avoided [58]. Intubated burn patients may have quantitative culture with bronchoalveolar lavage done to facilitate monitoring and early treatment of infectino [64–66]. Studies with postyploric feeding and silver-coated endotracheal tubes have conflicting results with regard to prevention of VAP, and thus require further investigation.

Cardiovascular

The section in this chapter on resuscitation discusses the post-burn hemodynamic changes in detail. To briefly recapitulate, microvascular changes after burn injury induce loss of plasma volume, increase peripheral vascular resistance, and decrease cardiac output immediately after injury. Additionally, circulating mediators, e. g., tumor necrosis alpha, impair cardiac contractility, as does perturbation in calcium utilization. These changes persist for at least 24 hours post-injury, but are nearly reversed with adequate resuscitation [1, 3, 8, 9]. For weeks to months after extensive burn injury, a prolonged release of catecholamines leads to a catabolic state with high cardiac output [20–22]. Propranolol can blunt the cardiac effects of this catecholamine surge, and prevent post-burn cardiomyopathy [49–50].

Renal

Acute kidney injury occurs in 25% of burn patients, and is associated with 35% mortality [67]. Among patients with frank kidney failure (class F according to the RIFLE scoring system), this mortality rate is even more dramatic, as high as 75% [67]. Prevention of death from kidney failure after burn injury hinges upon recognition of risk factors for azotemia, as well as support of kidney perfusion.

In one retrospective cohort study of 221, burn patients, 28% of cases of acute kidney injury arose during the resuscitative phase of treatment [68]. Hospital outcomes worsened among patients who developed renal failure during burn shock. Interestingly, the average urine output among patients who developed early acute kidney injury (AKI) was within the recommended range of 0.5–1.0 cc/kg/hr, revealing a disconnect between urine output and threat to kidney function. Patients who developed early AKI in this study had higher base deficits, indicating persistent shock despite apparently adequate urine output.

AKI likely arises from multifactorial sources in burn patients. Age, %TBSA, sepsis, and multi-organ failure independently increase the risk of AKI [67]. Studies in general critically-ill populations cite medications as responsible for up to 20% of cases of AKI [69]. Nephrotoxic agents to avoid in burn pa-

tients, or to be monitored stringently in the event of necessary administration, include aminoglycosides, colistin, amphotericin B (associated with a 25–30% risk of AKI), and Amicar. The kidneys are sensitive to changes in intra-abdominal pressure, and pressures greater than 12 mmHg can lead to AKI [69]. A sustained intra-abdominal pressure greater than 20 mmHg will generate AKI in more than 30% of cases [69]. Hyperglycemia has been associated with AKI, and physicians should strive to avoid excessive glucose eleveations. Intravenous contrast induces nephropathy, which can be avoided with volume expansionandthefreeradicalscavengeracetylcysteine. In the setting of injury, the kidneys lose the ability to autoregulate, and depend upon mean arterial pressure for perfusion. As a result, normotension among patients at risk for AKI, including the elderly, diabetics, patients with chronic kidney disease, and patients with hypertension at baseline is optimal. “Renally-dosed” dopamine, once given under the assumption that it optimized renal blood flow, does not reduce the incidence of AKI or the need for renal replacement therapy (RRT) [70]. In fact, data suggest that dopamine worsens renal perfusion, and is associated with increased myocardial strain and cardiac arrhythmias [70]. Fenoldepam, on the other hand, is a selective dopamin-1 receptor agonist that may increase renal blood flow at low doses ( > 1 mcg/kg/ min) without systemic effects. Data is conflicting – one prospective placebo-controlled study among septic patients showed no association between fenoldepam use and mortality, while meta-analyses suggest that fenoldepam decreases the need for RRT, and also decreases mortality among patients with AKI [71]. Precise indications for implementation of fenoldepam require further prospective study.

Diuretics may assist in management of volume overload and provide a temporizing therapy before implementation of RRT. Failure to respond to diuretics in AKI has been associated with an increased risk of death and renal non-recovery, however no evidence supports conversion of oliguric AKI to nonoliguric AKI with diuretics [69]. If patients develop severe hyperkalemia, clinical signs of uremia, severe acidosis, or volume overload refractory to diuresis, a nephrologist should be consulted for RRT, either through intermittent hemodialysis (HD) or continuous veno-venous hemofiltration (CVVH). For un-

stable, critically-ill patients, the latter of these options induces the least hemodynamic compromise. In terms of renal recovery, the extant data suggest that both methods are equitable, with no difference in mortality [69].

Gastrointestinal tract

The shock and reliance on vasopressor agents that accompany burn injury place patients at risk for mesenteric ischemia, which in turn increases patient’s susceptibility to bacteremia. The intestinal mucosa functions as a local defense barrier, preventing bacteria and endotoxin within the intestinal lumen from translocating into the circulatory system [72]. After burn resuscitation, splanchnic edema leads to peristalsis, with intestinal stasis, bacterial overgrowth, and compromise to the integrity of the mucosal barrier [72–75]. Vasoactive agents further damage the mucosal epithelium through a decrease in intestinal blood flow. The ischemic gut, itself, functions as a pro-inflammatory agent, releasing factors into the bloodstream that activate neutrophils and trigger end-organ dysfunction.

Immediate enteral feeding after thermal injury aids in maintenance of intestinal mucosa, and also thwarts the excessive release of catabolic hormones. Enteral feeding supports the structural integrity of the gut by maintaining mucosal mass, stimulating epithelial cell proliferation, maintaining villus height, and promoting the production of brush border enzymes [72–75]. Feeding stimulates mesenteric blood flow, and triggers the resealse of endogenous agents (e. g., cholecystikinin, gastrin, bile salts) that exert trophic effects on the epithelium [72, 73]. Patients fed early after burn injury also have significantly enhanced wound healing and shorter hospital stays, compared with controls [24].

Studies demonstrate that the protective effects of early feeding on the gut mucosa are not maintained with total parental nutrition (TPN). Studies in the 1980s revealed that despite the catabolic state and marked protein requirement of burn patients (1.5–2.0g/kg/day), aggressive high-calorie feeding with a combination of enteral feeds and supplemental TPN was associated with increased infectious complications and mortality [77, 78]. More recent investigations have not only confirmed these