Advances in burn critical care

Kyros Ipaktchi, MD; Saman Arbabi, MD, MPH

T reating patients with burninjuries requires a complex,multidimensional approach.Burn patients may have exten-

sive damage to skin, which may requiremultiple surgical interventions, burnwound management, physical and occu-pational therapy, and scar management.In the last decade, there have been majoradvances in this aspect of burn care,which includes early excision and graft-ing with autologous or allogeneic skin orbiosynthetic dermal substitutes (1). Al-though this approach has decreased mor-bidity and mortality, burn patients con-tinue to face many serious complications.Thermal insult may induce a major distur-bance in the homeostatic mechanisms,with severe disturbance in hemodynamic,respiratory, and metabolic pathways (2).Potential postburn complications are se-vere systemic inflammatory responsesyndrome, sepsis, acute respiratory dis-tress syndrome, multiple-system organfailure, and death. Addition of inhalationinjury may double the mortality rate andact as a synergistic insult on the pulmo-nary system (3). Physicians treating burn

patients face complex critical care issues.The present article will be a brief reporton some of the new advances in burncritical care. Rather than being all inclu-sive, we focused on four critical care issues:new approaches in management of respira-tory complications, advances in the resus-citation strategies, complex managementof the metabolic response to burns in-cluding nutritional support, and recentideas and approaches in immunotherapy.

AIRWAY MANAGEMENT ANDVENTILATORY STRATEGIES

Most severely burn-injured patientsare intubated early for airway manage-ment and respiratory support. Pulmonaryinsufficiency and failure in severelyburned patients is multifactorial. Thepathogenesis can be differentiated intodirect pulmonary and upper airway inha-lation injury and indirect or secondaryacute lung injury due to activation of thesystemic inflammatory response. There isalso secondary delayed pulmonary injurydue to sepsis and pneumonia. In addition,ventilator-associated lung injury hasbeen described as an important iatro-genic factor contributing to the second-ary accentuation of pulmonary injury (4).The reduced pulmonary compliance andchest wall rigidity of burn patients canlead to aggressive ventilatory manage-ment and high airway pressures, exacer-

bating acute lung injury. Institution oflow tidal volume ventilation, allowingpermissive hypercapnia, was shown to re-duce the development of ventilator-associated lung injury and significantlyimprove outcomes (4). In addition, use ofalternate ventilation strategies such ashigh-frequency oscillatory ventilationand high-frequency percussive ventila-tion may be beneficial in selected burnpatients (5). Although there are limitedcomparative data regarding these twostrategies, it seems that high-frequencypercussive ventilation is especially usefulin inhalation injuries (6). Extracorporealmembrane oxygenation is described bysome authors as an ultimate salvage op-tion in the pediatric population (7). Foradult patients, extracorporeal membraneoxygenation is to be considered when pa-tients face respiratory death from inhala-tion injury (8).

Adjunct therapies such as inhaled ni-tric oxide have gained momentum intreating hypoxic vasoconstriction in burnpatients, improving ventilation/perfusionmismatches and thereby tissue oxygen-ation (9, 10). In an animal model of in-halation injury, aerosolized heparin at-tenuated cellular infiltrates, lung edema,congestion, and cast formation and im-proved oxygenation (11). In a study of 90consecutive burn pediatric patients whohad inhalation injury, there was a signif-

From the University of Michigan Burn Center, AnnArbor, MI.

Copyright © 2006 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000232625.63460.D4

Background: Management of burn patients requires a complexinteraction of surgical, medical, critical care, and rehabilitationapproaches. Severe burn patients are some of the most challeng-ing critically ill patients who may have multiple-system organfailure with life-threatening complications.

Objective: To review and highlight some of the recent ad-vances in burn critical care. We focused on some of the newtreatment modalities in the management of respiratory complica-tions, advances in burn resuscitation, management of the meta-bolic response to burns, and recent ideas in burn immunotherapy.

Data Source: A search of the MEDLINE database and manualreview of published articles and abstracts from national andinternational meetings.

Data Syntheses and Conclusions: The respiratory management

of burn patients includes strategies to minimize iatrogenic injury withlow tidal volume ventilation, to improve ventilation/perfusion mis-match, and to diagnosis pneumonia. Many aspects of burn resusci-tation remain controversial, and the best form of fluid resuscitationhas yet to be identified. Recent research in the metabolic response tothermal injury has identified many potentially beneficial treatments.Although immunomodulation therapy is promising, currently most ofthese treatments are not clinically viable, and further clinical andtranslational research is warranted. (Crit Care Med 2006; 34[Suppl.]:S239–S244)

KEY WORDS: burn; critical care; inflammation; signal transduc-tion; mitogen-activated protein kinase (MAPK); adrenergic recep-tors; immunotherapy

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icant decrease in reintubation rates, in theprevalence of atelectasis, and in mortalityfor patients treated with the regimen ofaerosolized heparin and N-acetylcysteinewhen compared with controls (12).

Although most recent studies demon-strate improved outcomes with early tra-cheostomy, controversy still exists on thegeneral “optimal” tracheostomy tech-nique and timing (13). A retrospectivestudy of pediatric burn patients demon-strated that early tracheostomy was safe,provided a secure airway, and improvedthe ventilatory management of patients(14); but there was no significant changein oxygenation, minute ventilation, or pHafter tracheostomy. In a retrospective re-view of adult patients with severe burninjury, there were no differences in ven-tilatory support, length of stay, preva-lence of pneumonia, or survival (15);however, patients with tracheostomy hada significantly shorter time to extubation.Although there is controversy regardingimproved pneumonia rate and mortality,most researchers agree that tracheos-tomy offers some advantages in terms ofpatient comfort and security. Regardingthe preferred tracheostomy technique, re-cent studies demonstrate that percutane-ous tracheostomy may be safe in burn pa-tients (16, 17). Addition of fiberopticassistance may avoid rare but serious com-plications (18). The enthusiasm for percu-taneous tracheostomy should be temperedin patients with severe facial and neckburns or upper airway edema because lossof airway in these patients may be associ-ated with significant complications.

Pneumonia. Pneumonia is still one ofthe most common infectious complica-tions in severe burn patients. Ventilator-associated pneumonia is very common inburn patients, and similar to other criti-cally ill patients, it is associated with in-creased risk of fatal outcome (19, 20).Several factors prime burn victims forincreased susceptibility for pneumonia:relative immunosuppression, dysfunc-tional ciliary movement in inhalationalinjuries leading to impaired secretoryclearance, pulmonary inflammatory acti-vation with acute lung injury, and in-creased leakage of nutrient-rich plasmainto lung parenchyma. Due to severe un-derlying inflammatory pulmonary pa-thology, accurate clinical diagnosis ofventilator-associated pneumonia can bevery difficult in burn patients. The recentemergence of multi–drug-resistant bac-terial pathogens has mandated a more

accurate diagnosis of infectious compli-cations such as pneumonia. The NationalInfection Surveillance System uses phys-iologic data, laboratory evaluation, andradiographic data to define pneumonia.Recognizing the difficult diagnosis ofventilator-associated pneumonia in theinjured patients (21), many investigatorshave demonstrated the improved sensi-tivity and specificity by including quanti-tative cultures obtained via bronchoal-veolar lavage (22, 23). In a retrospectivereview of adult burn patients, the use ofbronchoalveolar lavage eliminated theunnecessary antibiotic treatment of 21%of patients and was associated with alower rate of ventilator-associated pneu-monia (24).

RESUSCITATION

Burn trauma leads to a combinationof hypovolemic and distributive shockon the basis of generalized microvascu-lar injury and interstitial third-spacingthrough collagen and matrix degenera-tion. Burn injury is marked by dynamicand ongoing fluid shifts, which have ledto the development of fluid resuscitationformulas based on percentage of totalbody surface area burn and weight. Fluidresuscitation based on the Parkland burnformula is extensively used in burn cen-ters and has helped minimize the occur-rence of burn shock (25). However, arecent survey of 28 burn centers foundthat in 58% of patients, actual fluid re-suscitation exceeded the 4 mL/kg recom-mended by Baxter and Shires (26). Over-resuscitation has been shown to correlatedirectly with increasing intraabdominalpressure and the development of abdom-inal compartment syndrome (27). Apartfrom the well-described extremity com-partment syndrome, orbital compart-ment syndrome requiring canthotomy inpatients receiving supranormal resuscita-tion was recently described (28). The cur-rent high-volume fluid regimens haveshifted postburn resuscitation complica-tions from renal failure to pulmonaryedema, with increased requirement forventilatory support, the need for fascioto-mies in unburned limbs, and the occur-rence of the abdominal compartmentsyndrome (29). The increased use of sed-ative and analgesic medication may havecontributed to increased fluid volumesgiven to burn patients. In essence, thependulum may have swung from insuffi-cient resuscitation to excessive volumeloading.

Crystalloid solutions, such as lactatedRingers solution and normal saline, arestill first-line fluid replacements in burnresuscitation. Due to reduced intravascu-lar fluid retention, large volumes haveto be infused, which accentuate tissueedema, and the development of tissueedema can lead to worsening outcomes(30). Hypertonic saline (HTS) resuscita-tion (7.5% NaCl) has been promoted forits efficient intravascular volume resusci-tation, rapid restoration of blood pressureand cardiac output with improved cere-bral perfusion, and potential for expand-ing circulating volume by reabsorption offluid from the interstitial space (31).More recently, HTS has been studied as afluid with significant modulation of sys-temic inflammatory response secondaryto reperfusion injury, which may be ben-eficial in patients with shock (32, 33). Inanimal models of trauma and burn, use ofHTS resuscitation has been associatedwith decreased edema and improved or-gan perfusion and outcomes (34 –36).Data on the effectiveness of HTS to pre-vent organ damage in the clinical settingare inconsistent (37). Some of the studiesin burn patients have demonstrated thatHTS may have decreased the fluid load,tissue edema, and complications such asabdominal compartment syndrome (38–40). But others have noted no benefit influid requirement and potential increaserisk of renal failure (41). It seems that thebenefit of HTS is seen in early resuscita-tion (42), and some researchers have rec-ommended stopping HTS infusion whenserum sodium concentration exceeds 160mEq/L (29, 43). Currently, HTS is notroutinely used in burn patients, and fur-ther research is required to better definepotential benefits, the timing, and theoptimal volume.

Theoretically, the use of colloids inresuscitation of hypovolemic patientsmay be associated with preservation ofplasma osmotic pressure, more efficientplasma volume expansion, and decreasedtissue and pulmonary edema. However,clinical studies have not demonstrated asignificant improvement in patient out-comes with colloid resuscitation (31, 44,45). In burn patients, treatment with al-bumin did not improve outcomes (44).

A prospective randomized study dem-onstrated that a restrictive strategy ofred-cell transfusion (hemoglobin concen-tration maintained at 7.0–9.0 g/dL) maybe superior to a liberal transfusion strat-egy (hemoglobin concentration main-tained at 10.0–12.0 g/dL) in critically ill

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patients, with the possible exception ofpatients with acute myocardial infarctionand unstable angina (46). A recent mul-tiple-center cohort analysis found an in-creased mortality in burn patients asso-ciated with blood transfusions (47).Therefore, there is a push to decreaseblood transfusion in burn patients. Re-combinant human erythropoietin hasbeen shown to be useful in treatment ofchronic anemia and, theoretically, maydecrease the need for blood transfusion inthe ICU. However, in a prospective, dou-ble-blind, randomized study of 40 se-verely burned patients, recombinant hu-man erythropoietin did not prevent thedevelopment of postburn anemia or de-crease transfusion requirements (48). In-terestingly, a recent animal study dem-onstrated that recombinant humanerythropoietin improved healing of burnwound through increased epithelial pro-liferation, maturation of the extracellularmatrix, and angiogenesis (49). Currently,most centers do not use erythropoietin intreatment of burn patients, and furtherclinical study is required before routineclinical use.

METABOLIC RESPONSE

During the flow phase postburn, thereis an impressive hyperdynamic response.For pediatric patient with �40% totalbody surface area burn, the resting met-abolic rate is increased in the ranges be-tween 160% and 200% (50). This globalhypermetabolism is associated withtachycardia, fever, muscle protein catab-olism, and derangement in hepatic pro-tein synthesis (51, 52). This response maybe associated with significant complica-tions such as immunodeficiency, im-paired wound healing, sepsis, loss of leanbody and muscle mass, cardiac ischemia,and potential death. Primary treatmentmodalities include avoidance of infec-tious complications such as sepsis andearly excision of full-thickness burns,which is associated with attenuation ofhypermetabolism (52–54). Several otherapproaches have been used to attenuatethe burn-induced hypermetabolism (54).This article will focus on early nutritionalsupport and modulation of hormonal/endocrine response.

Nutritional Support

The use of early enteral feeding inburn patients may attenuate catabolic re-sponse after thermal injury (55). Because

there is significant increase in energy ex-penditure after burns, high-calorie nutri-tional support was thought to decreasemuscle catabolism. However, aggressivehigh-calorie feeding with a combinationof enteral and parenteral nutrition wasassociated with increased mortality (56).Increasing enteral feeding beyond thebody energy expenditure, 20–40% abovethe resting energy expenditure, does notimprove lean body mass and is associatedwith complications such as fatty liver(51). Most authors recommend adequatecalorie intake via enteral feeding andavoidance of overfeeding (54).

High carbohydrate diets comparedwith high fat diets may improve the netbalance of skeletal muscle protein (57).Increased endogenous insulin may con-tribute to improved muscle metabolism.In a study of six adult patients with�40% total body surface area burn, treat-ment with insulin and metformin wereassociated with improved muscle kinetic(58). However, high carbohydrate dietmay be associated with elevated glucose,which may be detrimental in critically illpatients. In a study of 58 pediatric burnpatients, there was a significant associa-tion between poor glucose control andcomplications such as increased bactere-mia, reduced skin graft take, and in-creased mortality (59). In another study,tight glucose control in severe burn pa-tients seemed to be safe and associatedwith decreased risk of infection and im-proved survival (60). Therefore, aggres-sive monitoring and treatment of hyper-glycemia is recommended.

Similar to all critically ill patients, ad-equate protein intake is required. Be-cause there is an increased oxidation rateof amino acids in burn patients, the pro-tein requirement is increased to 1.5–2.0g/kg per day in treatment of severelyburned patients (54).

Modulation of Hormonal andEndocrine Response

Burn injury is associated with in-creased levels of catecholamines and cat-abolic hormones. Therefore, it is logicalto assume blockade of catecholamine re-sponse or use of anabolic steroids mayattenuate hypermetabolism or blunt cat-abolic response after burn injury. In thisreview, we will focus on beta-adrenergicreceptor blockade and oxandrolone.

Beta-Adrenergic Receptor Blockade.There has been a recent increased enthu-siasm for use of beta-blockers in treat-

ment of surgical patients. In elective non-cardiac operations, perioperativetreatment with beta-blockers has been as-sociated with reduced mortality and prev-alence of cardiovascular complications(61, 62). In burn patients, beta-blockerscan blunt the catecholamine effect by at-tenuating hypermetabolism, decreasingoxygen demand and resting energy ex-penditure, and decreasing heart rate andcardiac oxygen demand (54). Beta-blockers may also attenuate catechol-amine-induced muscle catabolism and li-polysis (63, 64). Moreover, there are datato suggest that beta-blockers can modifycatecholamine-mediated defect in lym-phocyte activation and improve immuneresponse with decreased infectious com-plications (65). Various studies have dem-onstrated the potential beneficial effect ofbeta-blockers in burn patients. Adminis-tration of propranolol (nonselective beta-antagonist) to burned children reducesthe release of free fatty acids from adiposetissue and decreases hepatic triacylglyc-erol storage and fat accumulation (66,67). In a randomized study of 25 childrenwith severe burns, treatment with pro-pranolol attenuated hypermetabolismand reversed muscle protein catabolism(68). In a retrospective study of adultburn patients, use of beta-blockers wasassociated with decreased mortality,wound infection rate, and wound healingtime (69). Although these data stronglysupport the use of beta-blockers in burnpatients, there are no large randomizedstudies looking at mortality and woundhealing in burn patients. Nevertheless,many burn units use beta-blockers suchas propranolol or metoprolol as the mosteffective catabolic treatment in burn pa-tients.

Oxandrolone. Oxandrolone is an ana-log of testosterone, which is an anabolichormone. It has been used to treat mus-cle wasting in various disease processessuch as acquired immune deficiency syn-drome (70). In a study of 14 severelyburned children, oxandrolone improvedmuscle protein metabolism through en-hanced protein synthesis efficiency (71).In adult burn patients, oxandrolone sig-nificantly decreased weight loss and netnitrogen loss and increased donor sitewound healing compared with placebocontrols (72). In a prospective random-ized study of 81 patients, 10 mg of oxan-drolone every 12 hrs was associated withdecreased hospital stay (73). Althoughthere was no hepatic insufficiency, a sig-nificant increase in hepatic transami-

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nases was observed. The authors recom-mended monitoring liver function testsin patients treated with oxandrolone.Enthusiasm to use oxandrolone shouldalso be tempered by the findings of po-tential increase in ventilatory days; in astudy of trauma patients, oxandrolonewas associated with increased ventila-tory days (74). The authors suggestedthat oxandrolone may enhance collagendeposition in acute respiratory distress.Overall, it seems that oxandrolone maybe beneficial in patients with large bodysurface area burns.

IMMUNOTHERAPY

Severe dermal burns are known to in-duce systemic inflammatory responsesyndrome, which is correlated with ahigh risk of end-organ failure (5, 75). Alsosevere burn injury is associated with in-creased risk of infection, sepsis, and im-munosuppression (76, 77). Therefore,many investigators have studied the ben-efit of immune modulation in severelyburned patients.

Immunonutrition. The immune-en-hancing diets/agents include arginine,glutamine, omega-3 fatty acids, and anti-oxidants such as ascorbic acid (vitamin C)and �-tocopherol (vitamin E). Multiplestudies looking at a combination diet ofthese agents have failed to demonstrate abenefit in critically ill patients (78, 79).The controversy regarding the use of im-mune-enhancing diets is ongoing, withmany studies showing benefit and othersshowing no improvement in outcomes.For instance, whereas many previousstudies support the use of glutamine sup-plementation, a recent study demon-strated that addition of glutamine to theenteral feed did not improve outcomes(80). Also, although many studies inburned animal models show improve-ment with a specific immune supplemen-tation, there are no human studies toinvestigate the response in a clinical set-ting. As an example, in burned rats, sup-plementation with omega-3 fatty acidsimproved protein metabolism and atten-uated muscle breakdown (81), but nolarge human trial has confirmed thesefinding in burned patients. Most re-searchers agree that an indiscriminateuse of a combination formula immu-nonutrition diet in critically ill patients isnot beneficial (78, 82). Therefore, a moreselective approach is proposed, and thereis a need for more clinical studies.

Use of high doses of ascorbic acid in

experimental burn-injured sheep was as-sociated with decreased edema and fluidrequirement (83). In a randomized trialof critically ill surgical patients, a combi-nation of ascorbic acid and �-tocopherolreduced the prevalence of organ failureand ICU length of stay (84). Early use ofhigh-dose antioxidant therapy in the in-jured patients seems to be beneficial;however, further clinical trials are re-quired to confirm this potential effect andbetter define the timing and the requireddose (85, 86).

Recombinant Human Activated Pro-tein C. Recombinant activated protein C(activated drotrecogin alfa) is the firstagent approved by the Food and DrugAdministration for treatment of severesepsis. The Protein C Worldwide Evalua-tion in Severe Sepsis (PROWESS) trialdemonstrated a statistically significantrelative risk reduction of 28-day mortality(87). Post hoc analyses of 532 possiblesurgical patients in the PROWESS trialdemonstrated a favorable benefit/riskprofile in surgical patients (88, 89). In-creased risk of bleeding was similar to themedical patients, and there was no fatalbleeding in the surgical cohort. Twenty-four patients in this group were definedas having a skin surgical procedurewithin 30 days before the study. Therewas a 12-hr waiting period after an oper-ation before starting the treatment.Other exclusion criteria for PROWESSwere pregnancy, recent cerebrovascularaccident, intracranial pathology, activebleeding, or anticipated need for surgerywithin the ensuing 96-hr period. Itshould also be noted that because 90% ofthe drug is eliminated within 2 hrs afterdiscontinuation of infusion, stopping thetreatment should rapidly stop drotreco-gin alfa–induced bleeding (88). Althoughthere are no published trials specificallyin burn patients, based on available infor-mation, burn patients with severe sepsiswho lack the exclusion criteria should beconsidered for recombinant activatedprotein C.

Topical Immunomodulation. Thermalinjury induces dermal inflammatory andpro-apoptotic signaling. In the absence ofinhalation injury, the burn wound is theinflammatory source triggering systemic in-flammatory response via liberation of aplethora of potentially deleterious proin-flammatory mediators and attraction/activation of neutrophils (90–92). Stud-ies using rodent models of thermal injuryhave demonstrated that controlling thesource of inflammation at the dermis

may attenuate systemic inflammatory re-sponse and acute lung injury (93, 94). Inthese studies, topical application of p38-mitogen–activated protein kinase inhibi-tor to the burn wound decreased dermalinflammation, postburn skin apoptosis,systemic inflammatory response, and sec-ondary pulmonary complications. Topicalinflammatory modulation in severe burnsis attractive because it can be readily usedin patients who are already receiving top-ical antimicrobial agents, and it mayavoid some of the systemic complica-tions. However, currently there are noclinically approved topical immuno-modulators for burn patients.

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