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The cardiovascular response to burn injury
Current Anaesthesia & Critical Care 19 (2008) 269–274
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FOCUS ON: BURNS CARE
The cardiovascular response to burn injury A. Jandziol*, M. Hayes Magill Department of Anaesthesia, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom
s u m m a r y Keywords: Burns Resuscitation Cardiovascular system Myocardium
Severe burn injury has a profound and widespread effect on an individuals cardiovascular system. Early features include myocardial contractile dysfunction and increased vascular permeability. This progresses to a hyperdynamic/hypermetabolic state with oxygen consumption increasing by up to 200%. Animal studies have suggested that pro-inflammatory mediators may in part be responsible, with TNF alpha, nuclear factor-kappa B, p38 activated protein kinase, macrophage inhibitory factor and high mobility group box 1 all playing a role. Traditional markers of myocardial injury are often unreliable in the presence of severe burn injury, either being too non-specific or having uncertain clinical significance. The restoration of adequate organ perfusion without the development of significant peripheral oedema is one of the primary goals of cardiovascular resuscitation in the burn patient. Despite the use of resuscitation formulae and various methods of assessing cardiac output and perfusion to aid resuscitation, the burn patient is often over or under resuscitated. Over resuscitation has led to severe tissue oedema resulting in impaired tissue perfusion and complications including compartment syndromes in unburned limbs and abdominal compartment syndrome. Vasopressors have a role in supporting the circulation, particularly during septic episodes, although caution must be taken as progression of burn wound depth may occur. B-Blockers are being increasingly used to attenuate the hypermetabolic state in burn patients with some promising results, particularly in the paediatric population. This review will focus on the cardiovascular responses to burn injury and discuss early fluid resuscitation and pharmacological support. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction The effect of a severe burn injury on the cardiovascular system has been observed and studied for some time. Classically the cardiovascular response has been thought to occur in 2 phases: an initial myocardial depressive or ‘Ebb’ phase which is accompanied by a profound increase in vascular permeability. This is followed by a hypermetabolic or ‘Flow’ phase. The two phases may be indistinct and there is often some overlap. Although the cardiovascular response to burn injury has been studied in human subjects, it has remained poorly understood. Recent animal work, however, has shown some light on the underlying mechanisms, demonstrating that the physiological responses are very similar to those seen in sepsis. 2. The cardiovascular response to burn injury It was suggested in 1931 by Blalock that impaired cardiovascular function was a major factor leading to organ failure following burn injury.1 Over the ensuing years a number of studies demonstrated
* Corresponding author. Tel.: þ44 208 746 8026; fax: þ44 208 746 8801. E-mail address: [email protected] (A. Jandziol). 0953-7112/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cacc.2008.10.001
that this impairment in cardiovascular function did not appear to mirror loss of circulating volume and also that volume resuscitation did not always improve left ventricular stroke work. In 1966, it was first proposed that a myocardial depressant factor was present following a severe burn injury to account for the myocardial dysfunction.2 Over the past decades, although few clinical studies have focussed on cardiac problems in patients with extensive burns, numerous animal studies have been performed to confirm this myocardial contractile dysfunction.3 Important observations from these studies, have demonstrated that it occurs very early after the burn injury and resolves up to 72 h later.4 It remains unclear how important it is clinically to the burn patient, it may be insignificant for the young and previously healthy, but have more consequence for the older and those with co-morbidity. It is noteworthy that during this period, those patients who can achieve a greater cardiac output and greater oxygen delivery in response to fluid resuscitation are more likely to survive the burn injury.5 This has been demonstrated previously in other critically ill patients including those with sepsis and trauma.6–8 It is unclear as to whether the survivors have a greater cardiac reserve or less severe cytokine response to the burn injury. Following the above period of myocardial dysfunction, provided there has been adequate fluid resuscitation, the patient develops a hypermetabolic state with a hyperdynamic circulation. In this state
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the cardiac output is high, there is a low systemic vascular resistance and the oxygen consumption may increase by up to 200%.9 There is also an associated tachycardia, fever, increased muscle breakdown and derangement in hepatic protein synthesis.10,11 In this phase they are at great risk of septic complications and death. Following major burns, an inflammatory cascade is triggered, the outcome of which is dependant on the balance between the pro and anti inflammatory mediators. Hypovolaemia associated with persisting capillary leakage rather than myocardial depression has been suggested as the cause of the impaired myocardial performance during the early period post burn injury.12 Other studies, however, have suggested that it is the secretion of pro-inflammatory mediators by the cardiomyocyte that lead to the early myocardial dysfunction and it is believed that TNF alpha plays an early significant role. It has been shown that TNF alpha can directly cause cardiac dysfunction and failure in mice13 and other work has confirmed it’s cardiodepressant effects by direct application to the isolated cardiomyocyte.14 The contractile defects may be as a result of cardiac myocyte apoptosis15 which has been identified as a mechanism of cell death in acute myocardial infarction and ischaemia reperfusion injury. TNF alpha may also mediate organ dysfunction through the synthesis of nitric oxide (NO).16,17 NO may combine with superoxide forming peroxynitrite a highly cytotoxic oxidant. Two of the most important factors that have been shown to regulate induction of TNF alpha are nuclear factor-kappa B (NF-kB) and p38 activated protein kinase (MAPK).18 In burns greater than 40% body surface area, there is a significant increase in MAPK activity and myocardial NF-kB levels.19,20 Other factors produced later in the inflammatory cascade that may lead to myocardial depression following burn injury are macrophage inhibitory factor (MIF) and high mobility group box 1 (HMGB1).20 MIF modulates the cell signalling path that controls inflammatory cytokine release by the cardiomyocytes and also may have a direct effect on the cardiomyocyte.21,22 The administration of HMGB1 to mice led to sepsis like symptoms and death.23 Other mediators of interest are the heat shock proteins (HSP) and capsases. HSPs have a cardioprotective effect, therefore a mechanism of cardiac dysfunction after burn injury may be due to the inhibition of the expression of HSPs.20 Capsases play a role in apoptosis and regulation of the inflammatory pathway.20 Over 20 years ago, it was shown that early excision of burns improved survival24 and can also prevent the increase in oxygen consumption seen post burn injury.25 Despite this, however, the effect of early excision on myocardial inflammation and contractility has not yet been studied in human subjects. A recent animal study has demonstrated a significant reduction in myocardial inflammation by demonstrating a reduction in cardiac myocyte secretion of TNFa, IL-1B, IL-6 and IL-10 when rats with 20% and 30%
Total Body Surface Area (TBSA) burns underwent early excision and grafting within 30 min of the injury.26 Rats who underwent early excision also demonstrated significantly improved cardiac function. This suggests that the burn wound itself is at least partially responsible for the production of mediators which contribute to myocardial inflammation and dysfunction. Optimal timing of early excision and grafting remains unknown, but if it could occur it may reduce the release of inflammatory mediators and thereby the risk of organ dysfunction and death. Due to the large amount of muscle and soft tissue damage that is often present in burn injury, markers that have been previously used as an indicator of cardiac injury (lactate dehydrogenase, creatinine phosphokinase and its MB isoenzyme (CK-MB) lack the specificity to be clinically useful. Cardiac Troponin-I (cTnI) is a regulatory protein of cardiac muscle contraction and exists in the myocyte in both protein-bound and functionally unbound forms. It is known to be a highly specific and sensitive indicator of myocardial injury. Not surprisingly cardiac troponin-I has been found to be raised in patients with a burn injury. This rise occurs in burn injuries of TBSA 20% or more, as early as 3 h post injury, the level peaks at 12 h and remains raised for more than 24 h.27 Raised cTnI levels have been detected for up to 14 days post burn, with higher levels detected in burns greater than 30% TBSA. Increasing cTnI levels have also been found to be related to the patient’s clinical condition, with higher levels found in patients with obvious burn wound exudation or spontaneous separation of the eschar with accompanying signs of sepsis. After surgical excision of the wound, cTnI levels have been shown to decrease over a period of 2–3 days.28 Whether this degree of myocardial injury, as shown by leakage of cTnI from myocytes into the circulation and measured by raised cTnI values, has any impact on outcome has yet to be established. Cardiomyopathy is a rare but important late cardiovascular complication in patients who suffer severe burns, and can occur greater than 30 days and up to 6 months after injury.29 Impaired systolic function and ventricular dilatation can result in congestive cardiac failure with a significant morbidity and mortality. The cardiomyopathy does not appear to be caused by irreversible structural abnormalities (more likely due to circulating inflammatory mediators) and with treatment cardiac function can eventually return to normal over a period of several months.30 3. Resuscitation 3.1. Goals for treatment The goals for burns resuscitation are broadly the restoration of adequate organ and peripheral perfusion without the development of significant peripheral oedema. In the first instance fluid
Table 1 Resuscitation formula to guide fluid resuscitation in burns injury
Parkland Modified Brooke Glaveston (Paediatric)
Evans
Crystalloid
Colloid
Other
Time Period
Lactated Ringer’s 4 ml/ kg/%BSA burned Lactated Ringer’s 2 ml/ kg/%BSA burned Lactated Ringer’s (for Burn) 5000 ml/m2 BSA Burn Saline 1 ml/kg/% BSA burned
–
–
–
–
–
Lactated Ringer’s (maintenance) 2000 ml/m2 TBSA Water (Dextrose) 2000 ml
Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h) Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h) Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h)
(Blood/Dextran/Plasma) 1 ml/ kg/%BSA burned
Brooke
Lactated Ringer’s 1.5 ml/kg/%BSA burned
(Blood/Dextran/Plasma) 0.5 ml/ kg/%BSA burned
Water (Dextrose) 2000 ml
Muir and Barkley
–
‘‘Plasma ration’’ ¼ 1ml per (%BSA burned/kg)/2
–
Given over 24 h, then 1/2 again over second 24 h (not to give more fluid than 50% TBSA burn) Given over 24 h, then 1/2 again over second 24 h (not to give more fluid than 50% TBSA burn) 6 rations given over 36 h (3 rations then 2 rations then 1 ration, over succesive 12 h intervals)
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resuscitation needs to be aggressive to reverse shock, however, it is unclear what the end points of resuscitation should be and at present they are poorly defined. Formulae have been developed over the years, Table 1, to guide initial resuscitation and further fluid is given if necessary to attain normal haemodynamic parameters and a urine output of generally between 0.5 and 1 ml/kg/h. 3.2. Monitoring haemodynamics There has been a tendency to stay away from invasive methods of monitoring cardiac function such as the pulmonary artery catheter, as there is a high risk of complications particularly if left in place for more than 3 days. Although work has demonstrated that survivors of critically illness have greater cardiac output, oxygen delivery and oxygen consumption than non-survivors there is no evidence that treating these patients to try and achieve these supranormal levels improves outcome.31 There may be situations, however, when further haemodynamic monitoring may be advantageous as they may indicate compensated shock and inadequate tissue perfusion, particularly in those who have limited cardiac reserve. The advent, therefore, of less invasive methods of monitoring such as transpulmonary thermodilution, the PiCCO, the lithium dilution cardiac output device (LiDCO) and the oesophageal Doppler may help and with time their roles may become more defined. Transpulmonary thermodilution derives cardiac output (both right and left ventricular output) from a computerised analysis of the arterial thermodilution curve. It is also able to give an estimate for total circulating blood volume and intrathoracic blood volume. In the double indicator technique, an indicator dye is mixed with a cold injectate to improve accuracy. The technique requires central venous access, through which the injectate is given as a bolus, and a special thermistor tipped fibreoptic catheter inserted into a femoral artery (which also acts as an arterial pressure sensor). As most acute burns patients require central venous and arterial pressure monitoring this presents no additional burden in terms of additional intravascular cannulation. Using this double indicator technique of transpulmonary themodilution during burns resuscitation, there has been shown to be a good correlation between the intrathoracic blood volume (ITBV) with both cardiac index and oxygen delivery (DO2).32 Kuntscher et al. also demonstrated that the total circulating blood volume index (TBVI) correlated well with cardiac index and stroke volume during major burns resuscitation,33 implying that restoring the ‘measured’ circulating volume could restore cardiac function. Using this technique, aiming for a intrathoracic blood volume index (ITBVI) above 800 ml/m2 and a cardiac index of >3.5 l/min/m2, results in more aggressive fluid resuscitation, higher urine output and a greater cardiac output at 24 h.32 The double indicator thermodilution technique appears to be a very useful, reproducible34 and accurate35 method of measuring cardiac output and O2 delivery in the burns population, but unfortunately, as of yet, there is no evidence to show that its use is associated with a beneficial effect on outcome. The PiCCO technology is based on the transpulmonary thermodilution technique and provides minimally invasive continuous monitoring of haemodynamic and volumetric parameters. Instead of using a double indicator solution, the PiCCO uses a single thermodilution technique of cold injectate, which is bolused through central venous access and is measured by a special thermistor tipped arterial cannula (femoral, brachial or axillary). As well as providing haemodynamic variables the single thermodilution technique is used to calibrate the arterial pulse contour analysis, which then provides continuous haemodynamic data. The PiCCO has been shown to have a very good correlation with pulmonary artery catheter measurement at normal to low CI, but at a higher CI (>5.5 l/min/m2) the correlation is not as good.36 Unfortunately the
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precision of ITBVI measurements using this technique is poor and hence cannot be used accurately to guide volume resuscitation.37 The LiDCOÔplus is another system which uses an indicator dilution technique for the measurement of cardiac output. A small dose of lithium chloride is given into a central venous cannula or into a peripheral line if central access is not available. Blood is then sampled from an attachment to an existing standard arterial line and the concentration-time curve of the lithium is measured. This information is used to calculate the absolute cardiac output value and to calibrate the pulse contour analysis. The software then analyses the arterial blood pressure trace and calculates the beat to beat ‘real-time’ cardiac output, with recalibration recommended every 8 h there after. There is currently no trial data on the use of LiDCOÔplus in burns patients, although the system has gained popularity due to its ease of use and its ability to use existing vascular access. The system has been studied in animal models although there is currently little work in critically ill patients. The lithium indicator dilution technique appears to have a good correlation with cardiac output measurement compared with the PAC thermodilution method, and variables such as pulse pressure, systolic pressure and stroke volume variations that occur during the respiratory cycle in ventilated patients have been shown to be reliable dynamic markers of ‘fluid responsiveness’.38,39 As with all methods that use pulse contour analysis, the LiDCOÔplus’s accuracy is affected by arterial waveform artefacts such as dampening of the waveform, severe vasoconstriction causing changes in waveform morphology and by irregular pulse rates (especially changes during calibration). Its calibration is also effected by nondepolarising muscle relaxants. Oesphageal Doppler monitoring has also gained some popularity due to its relative ease of use, minimal invasiveness and ability to provide real-time cardiac output data. The technique uses a probe which measures velocity of blood flow in the descending aorta, then using an estimate of aortic cross sectional area various cardiac indices can be calculated. When compared to PAC monitoring during major escharotomy, oesophageal Doppler monitoring has been shown to consistently underestimate cardiac output hence it does not provide accurate absolute values. It is, however, reliably able to show real time changes in volume status.40 3.3. Haemodynamics/biochemistry A large base deficit and elevated lactate levels have been shown to predict mortality in burns patients, particularly in those patients in whom the levels do not return to baseline with resuscitation.41 While a significant base deficit is likely to be related to poor perfusion, there is concern that an elevated lactate may not be a predictor of poor resuscitation but an indicator of burn size. It is unknown whether resuscitation directed at early correction of either base deficit or lactate would lead to less organ dysfunction and an improved outcome, although it is well recognised that persistent unrecognised tissue ischaemia can lead to systemic inflammation and organ failure. 3.4. Fluids Fluids used in initial resuscitation tend to be crystalloid such as Hartmann’s or normal saline and various formulae such as the Parkland formula are used in different burns centres. All provide a guide for resuscitation but fluids need to be adjusted dependant on the patient’s clinical state and may need to be increased if there is an inhalation injury or other coexisting injuries. Under resuscitation and obviously hypovolaemia will occur after large burns if not enough fluid resuscitation is provided but excess fluid will
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worsen tissue oedema. Many units do end up giving more fluids than that which is recommended by formulae and there is therefore concern that over administration of fluids (fluid creep)42 can lead to serious exacerbation of tissue oedema and impaired tissue oxygen utilisation. This oedema can lead to compartment syndromes which may require escharotomy or fasciotomy and may also lead to intra-abdominal hypertension. Intra-abdominal pressures in excess of 30 cm H20 indicate intra-abdominal hypertension (IAH). If left untreated it can lead to acute renal failure, pulmonary dysfunction, reduced cardiac output, splanchnic ischaemia and intracranial hypertension. If IAH is present with a tense abdomen together with either oliguria (despite aggressive fluid resuscitation) or high peak inspiratory pressures (that compromise ventilation) then a diagnosis of abdominal compartment syndrome can be made. Recent reports suggest that the critical volume associated with intra-abdominal hypertension is approximately 300 ml/kg/24 h.43 It has been suggested that the volume of fluid administered following serious burn injuries is increasing as a result of using base deficit rather than urine output as an endpoint, the increased use of opiates and sedatives has also been blamed. It is also possible that transfer to regional units may be a factor, as delayed resuscitation leads to an increase in fluid requirements. It is interesting that a recent paper demonstrated that resuscitation to ITBV end points using the PiCCO rather than to urine output could actually lead to less fluid administration, less oedema formation and less organ dysfunction. This was termed ‘permissive hypovolaemia’.44 3.5. Which fluid The use of colloids in resuscitation remains controversial as studies have not demonstrated any significant improvements in outcome with their use, although less volume may be required for resuscitation leading to less tissue oedema. Some units will give human albumin after 12–24 h if the patient remains under resuscitated,45 however, there was no reduction in multiple organ dysfunction when 5% human albumin was used for resuscitation for adult burn shock.46 In fact a Cochrane review stated recently that as colloids are not associated with an improvement in survival, and as they are more expensive than crystalloids, it is hard to see how their continued use in critically ill patients (including those with burns) can be justified outside the context of randomised, controlled trials.47 Hypertonic saline (7.5% NaCl) may also be of benefit, as in animal models its use has been associated with improved organ perfusion and outcome and it has been shown to enhance host defence to bacterial challenge in mice.48 In adults its use may lead to a reduced total colume, less tissue oedema and a decreased incidence of abdominal compartment syndrome, although this is controversial. There is concern about a potentially increased risk of renal failure.49 It is currently not routinely used. 4. Pharmacological support
Unfortunately use of any vasopressor may lead to progression of the burn wound depth. 4.2. Steroids In septic, burn patients corticosteroids may improve vascular reactivity and allow a reduction in vasopressor dose. There may also be benefit in the presence of impaired adrenocortical function, but it is presently difficult to identify which patients may benefit. It may not be justifiable in view of risks of immune suppression and infection associated with their use. In a recent paper hydrocortisone did not improve survival in patients with septic shock.51 4.3. B-Blockers Once resuscitation is complete following the burn injury, the metabolic rate starts to increase and then reaches a peak up to 2 weeks later. Patients with burns greater than 40% are always catabolic and those with less severe burns will become catabolic with sepsis. This hypermetabolic response typically lasts for 9–12 months post burn and is associated with: severe protein loss increased infection risk impaired wound healing B-Blockers can attenuate this hypermetabolic state but the mechanism of action is unclear. It may be due to enhanced protein synthesis. In a group of 25 children with acute, severe burns of more than 40% TBSA, 12 received oral propranolol to reduce the resting heart rate by 20%. In this group the net muscle-protein balance increased by 82% over baseline values, whilst it fell by 27% in the control group. The fat free mass also significantly decreased in the control group but was mostly unchanged in the protocol group.52 B-Blocker treatment in burned children has been shown to reverse protein catabolism which results in an improved nutritional status.52 It also leads to a lower glucose level and reduced lypolysis53 which leads to less fatty infiltration of the liver. There is also a lower heart rate with a maintained cardiac output due to improved left ventricular filling and stroke volume.54 It has also been suggested that the administration of B-Blockers may improve outcome in adult burns patients.55 Although many burns units use beta blockers to attenuate the hypermetabolic response there is at present no randomised trial looking at outcome in this group of patients. There is also evidence that catecholamines are necessary to fight infections. It has previously been demonstrated that adrenaline enhances platelet neutrophil adhesion in vitro56 and noradrenaline maintains the phagocytic function of macrophages at optimal levels.57 There has therefore been concern that beta blockade may cause a detrimental effect. In a recent study of 245 paediatric burns patients, however, propranolol resulted in an attenuation of hypermetabolism and there was no increase in the incidence of sepsis in the propranolol treated group.58 There was also no significant difference in mortality between the two groups.
4.1. Vasopressors 4.4. Growth hormone Noradrenaline is commonly used to increase blood pressure in septic burns patients, and inotropic agents may be beneficial if there is significant myocardial depression. Determining which patients may benefit may help to improve outcome. There has been recent interest in the use of vasopressin, which was found to be an effective agent that increased blood pressure in septic burns patients who were already receiving noradrenaline.50 Vasopressin had a noradrenaline sparing effect.
Growth hormone is a potent anabolic agent. In a healthy adult population growth hormone has been shown to enhance cardiac performance. In burned children, as well as improving height, weight and lean body mass, long term growth hormone therapy has also been found to significantly improve left ventricular ejection fraction for 12 months after burn injury, although a possible benefit on overall
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cardiac function has yet to be shown.59 Growth hormone, however, has some serious adverse effects. It can lead to hyperglycaemia and has led to an increased mortality in critically ill adult patients.60 This worsened outcome was not seen in paediatric patients.61
24. 25. 26.
5. Conclusion 27.
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Arterial thermodilution: an alternative to pulmonary artery catheter for cardiac output assessment in burn patients. Burns 2001;27:161–6. Ku¨ntscher MV, Blome-Eberwein S, Pelzer M, Erdmann D, Germann G. Transcardiopulmonary vs pulmonary arterial thermodilution methods for haemodynamic monitoring of burned patients. J Burn Care Rehabil 2002;23:21–6. Ku¨ntscher MV, Czermak C, Blome-Eberwein S, Dacho A, Germann G. Transcardiopulmonary thermal dye versus single thermodilution methods of assessment of intrathoracic blood volume and extravascular lung water in major burn resuscitation. J Burn Care Rehabil 2003;24(3):142–7. Pearse RM, Ikram K, Barry J. Equipment review: an appraisal of the LiDCOÔplus method of measuring cardiac output. Crit Care 2004;8(3):190–5. Jonas MM, Tanser S. Lithium dilution measurement of cardiac output and arterial pulse waveform analysis: an indicator dilution calibrated beat-by-beat system for continuous estimation of cardiac output. Curr Opin Crit Care 2002;8:257–61. Kim K, Kwok I, Chang H, Han T. Comparison of cardiac outputs of major burn patients undergoing extensive early escharotomy: esophageal Doppler monitor versus thermodilution pulmonary artery catheter. J Trauma 2004;57:1013–7. Andel D, Kamolz LP, Roka J, Schramm W, Zimpfer M, Frey M, et al. Base deficit and lactate: early predictors of morbidity and mortality in patients with burns. Burns 2007;33:973–8. Saffle J. The phenomenon of ‘‘fluid creep’’ in acute burn resuscitation. J Burn Care Res 2007;28:382–95. Oda J, Yamashita K, Inoue T, Harunari N, Ode Y, Mega K, et al. Resuscitation fluid volume and abdominal compartment syndrome in patients with major burns. Burns 2006;32:151–4. Arlati S, Storti E, Pradella V, Bucci L, Vitolo A, Pulici M. Decreased fluid volume to reduce organ damage: a new approach to burn shock resuscitation? A preliminary study. Resuscitation 2007;72:371–8. Greenhalgh DG. Burn resuscitation. J Burn Care Res 2007;28:555–65. Cooper AB, Cohn SM, Zhang HS, Hanna K, Stewart TE, Slutsky AS, ALBUR Investigators. Five percent albumin for adult burn shock resuscitation: lack of effect on daily multiple organ dysfunction score. Transfusion 2006;46: 80–9. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2007;(4). CD000567. Chen LW, Huang HL, Lee IT, Hsu CM, Lu PJ. Hypertonic saline enhances host defence to bacterial challenge by augmenting toll-like receptors. Crit Care Med 2006;34:1758–68. Huang PP, Stucky FS, Dimick AR, Treat RC, Bessey PQ, Rue LW. Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg 1995;221:543–54. Cartotto R, McGibney K, Smith T, Abidir A. Vasopressin for the septic burn patient. Burns 2007;33:441–51. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al, CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111–24. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta blockade after severe burns. N Engl J Med 2001;345:1223–9. Herndon DN, Nguyen TT, Wolfe RR, Maggi SP, Biolo G, Muller M, et al. Lipolysis in burned patients is stimulated by the beta 2-receptor for catecholamines. Arch Surg 1994;129:1301–4.
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54. Herndon DN, Barrow RE, Rutan TC, Minifee P, Jahoor F, Wolfe RR. Effect of propranolol administration on haemodynamics and metabolic responses of burned paediatric patients. Ann Surg 1988;208:484–92. 55. Arbabi S, Ahrns KS, Wahl WL, Hemmila MR, Wang SC, Brandt MM, et al. Beta-Blocker use is associated with improved outcomes in adult burn patients. J Trauma 2004;56:265–71. 56. Horn NA, Anastase DM, Hecker KE, Baumert JH, Robitzsch T, Rossaint R. Epinephrine enhances platelet-neutrophil adhesion in whole blood in vitro. Anaesth Analg 2005;100:520–6. 57. Garcia JJ, Del Carmen Saez M, De La Fuente M, Ortega E. Regulation of phagocytic process of macrophages by noradrenaline and its end metabolite 4-hydroxy-3-metoxyphenyl-glycol. Role of alpha and beta adrenoreceptors. Mol Cell Biochem 2003;254:299–304.
58. Jeschke MG, Norbury WB, Finnerty CC, Branski LK, Herndon DN. Propranolol does not increase inflammation, sepsis or infectious episodes in severely burned children. J Trauma 2007;62:676–81. 59. Mlcak RP, Suman OE, Murphy K. Effects of growth hormone on anthropometric measurements and cardiac function in children with thermal injury. Burns 2005;31:60–6. 60. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785–92. 61. Herndon DN, Barrow RE, Kunkel KR, Broemeling L, Rutan RL. Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990;212:424–9.
Contents lists available at ScienceDirect
Current Anaesthesia & Critical Care journal homepage: www.elsevier.com/locate/cacc
FOCUS ON: BURNS CARE
The cardiovascular response to burn injury A. Jandziol*, M. Hayes Magill Department of Anaesthesia, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom
s u m m a r y Keywords: Burns Resuscitation Cardiovascular system Myocardium
Severe burn injury has a profound and widespread effect on an individuals cardiovascular system. Early features include myocardial contractile dysfunction and increased vascular permeability. This progresses to a hyperdynamic/hypermetabolic state with oxygen consumption increasing by up to 200%. Animal studies have suggested that pro-inflammatory mediators may in part be responsible, with TNF alpha, nuclear factor-kappa B, p38 activated protein kinase, macrophage inhibitory factor and high mobility group box 1 all playing a role. Traditional markers of myocardial injury are often unreliable in the presence of severe burn injury, either being too non-specific or having uncertain clinical significance. The restoration of adequate organ perfusion without the development of significant peripheral oedema is one of the primary goals of cardiovascular resuscitation in the burn patient. Despite the use of resuscitation formulae and various methods of assessing cardiac output and perfusion to aid resuscitation, the burn patient is often over or under resuscitated. Over resuscitation has led to severe tissue oedema resulting in impaired tissue perfusion and complications including compartment syndromes in unburned limbs and abdominal compartment syndrome. Vasopressors have a role in supporting the circulation, particularly during septic episodes, although caution must be taken as progression of burn wound depth may occur. B-Blockers are being increasingly used to attenuate the hypermetabolic state in burn patients with some promising results, particularly in the paediatric population. This review will focus on the cardiovascular responses to burn injury and discuss early fluid resuscitation and pharmacological support. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction The effect of a severe burn injury on the cardiovascular system has been observed and studied for some time. Classically the cardiovascular response has been thought to occur in 2 phases: an initial myocardial depressive or ‘Ebb’ phase which is accompanied by a profound increase in vascular permeability. This is followed by a hypermetabolic or ‘Flow’ phase. The two phases may be indistinct and there is often some overlap. Although the cardiovascular response to burn injury has been studied in human subjects, it has remained poorly understood. Recent animal work, however, has shown some light on the underlying mechanisms, demonstrating that the physiological responses are very similar to those seen in sepsis. 2. The cardiovascular response to burn injury It was suggested in 1931 by Blalock that impaired cardiovascular function was a major factor leading to organ failure following burn injury.1 Over the ensuing years a number of studies demonstrated
* Corresponding author. Tel.: þ44 208 746 8026; fax: þ44 208 746 8801. E-mail address: [email protected] (A. Jandziol). 0953-7112/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cacc.2008.10.001
that this impairment in cardiovascular function did not appear to mirror loss of circulating volume and also that volume resuscitation did not always improve left ventricular stroke work. In 1966, it was first proposed that a myocardial depressant factor was present following a severe burn injury to account for the myocardial dysfunction.2 Over the past decades, although few clinical studies have focussed on cardiac problems in patients with extensive burns, numerous animal studies have been performed to confirm this myocardial contractile dysfunction.3 Important observations from these studies, have demonstrated that it occurs very early after the burn injury and resolves up to 72 h later.4 It remains unclear how important it is clinically to the burn patient, it may be insignificant for the young and previously healthy, but have more consequence for the older and those with co-morbidity. It is noteworthy that during this period, those patients who can achieve a greater cardiac output and greater oxygen delivery in response to fluid resuscitation are more likely to survive the burn injury.5 This has been demonstrated previously in other critically ill patients including those with sepsis and trauma.6–8 It is unclear as to whether the survivors have a greater cardiac reserve or less severe cytokine response to the burn injury. Following the above period of myocardial dysfunction, provided there has been adequate fluid resuscitation, the patient develops a hypermetabolic state with a hyperdynamic circulation. In this state
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the cardiac output is high, there is a low systemic vascular resistance and the oxygen consumption may increase by up to 200%.9 There is also an associated tachycardia, fever, increased muscle breakdown and derangement in hepatic protein synthesis.10,11 In this phase they are at great risk of septic complications and death. Following major burns, an inflammatory cascade is triggered, the outcome of which is dependant on the balance between the pro and anti inflammatory mediators. Hypovolaemia associated with persisting capillary leakage rather than myocardial depression has been suggested as the cause of the impaired myocardial performance during the early period post burn injury.12 Other studies, however, have suggested that it is the secretion of pro-inflammatory mediators by the cardiomyocyte that lead to the early myocardial dysfunction and it is believed that TNF alpha plays an early significant role. It has been shown that TNF alpha can directly cause cardiac dysfunction and failure in mice13 and other work has confirmed it’s cardiodepressant effects by direct application to the isolated cardiomyocyte.14 The contractile defects may be as a result of cardiac myocyte apoptosis15 which has been identified as a mechanism of cell death in acute myocardial infarction and ischaemia reperfusion injury. TNF alpha may also mediate organ dysfunction through the synthesis of nitric oxide (NO).16,17 NO may combine with superoxide forming peroxynitrite a highly cytotoxic oxidant. Two of the most important factors that have been shown to regulate induction of TNF alpha are nuclear factor-kappa B (NF-kB) and p38 activated protein kinase (MAPK).18 In burns greater than 40% body surface area, there is a significant increase in MAPK activity and myocardial NF-kB levels.19,20 Other factors produced later in the inflammatory cascade that may lead to myocardial depression following burn injury are macrophage inhibitory factor (MIF) and high mobility group box 1 (HMGB1).20 MIF modulates the cell signalling path that controls inflammatory cytokine release by the cardiomyocytes and also may have a direct effect on the cardiomyocyte.21,22 The administration of HMGB1 to mice led to sepsis like symptoms and death.23 Other mediators of interest are the heat shock proteins (HSP) and capsases. HSPs have a cardioprotective effect, therefore a mechanism of cardiac dysfunction after burn injury may be due to the inhibition of the expression of HSPs.20 Capsases play a role in apoptosis and regulation of the inflammatory pathway.20 Over 20 years ago, it was shown that early excision of burns improved survival24 and can also prevent the increase in oxygen consumption seen post burn injury.25 Despite this, however, the effect of early excision on myocardial inflammation and contractility has not yet been studied in human subjects. A recent animal study has demonstrated a significant reduction in myocardial inflammation by demonstrating a reduction in cardiac myocyte secretion of TNFa, IL-1B, IL-6 and IL-10 when rats with 20% and 30%
Total Body Surface Area (TBSA) burns underwent early excision and grafting within 30 min of the injury.26 Rats who underwent early excision also demonstrated significantly improved cardiac function. This suggests that the burn wound itself is at least partially responsible for the production of mediators which contribute to myocardial inflammation and dysfunction. Optimal timing of early excision and grafting remains unknown, but if it could occur it may reduce the release of inflammatory mediators and thereby the risk of organ dysfunction and death. Due to the large amount of muscle and soft tissue damage that is often present in burn injury, markers that have been previously used as an indicator of cardiac injury (lactate dehydrogenase, creatinine phosphokinase and its MB isoenzyme (CK-MB) lack the specificity to be clinically useful. Cardiac Troponin-I (cTnI) is a regulatory protein of cardiac muscle contraction and exists in the myocyte in both protein-bound and functionally unbound forms. It is known to be a highly specific and sensitive indicator of myocardial injury. Not surprisingly cardiac troponin-I has been found to be raised in patients with a burn injury. This rise occurs in burn injuries of TBSA 20% or more, as early as 3 h post injury, the level peaks at 12 h and remains raised for more than 24 h.27 Raised cTnI levels have been detected for up to 14 days post burn, with higher levels detected in burns greater than 30% TBSA. Increasing cTnI levels have also been found to be related to the patient’s clinical condition, with higher levels found in patients with obvious burn wound exudation or spontaneous separation of the eschar with accompanying signs of sepsis. After surgical excision of the wound, cTnI levels have been shown to decrease over a period of 2–3 days.28 Whether this degree of myocardial injury, as shown by leakage of cTnI from myocytes into the circulation and measured by raised cTnI values, has any impact on outcome has yet to be established. Cardiomyopathy is a rare but important late cardiovascular complication in patients who suffer severe burns, and can occur greater than 30 days and up to 6 months after injury.29 Impaired systolic function and ventricular dilatation can result in congestive cardiac failure with a significant morbidity and mortality. The cardiomyopathy does not appear to be caused by irreversible structural abnormalities (more likely due to circulating inflammatory mediators) and with treatment cardiac function can eventually return to normal over a period of several months.30 3. Resuscitation 3.1. Goals for treatment The goals for burns resuscitation are broadly the restoration of adequate organ and peripheral perfusion without the development of significant peripheral oedema. In the first instance fluid
Table 1 Resuscitation formula to guide fluid resuscitation in burns injury
Parkland Modified Brooke Glaveston (Paediatric)
Evans
Crystalloid
Colloid
Other
Time Period
Lactated Ringer’s 4 ml/ kg/%BSA burned Lactated Ringer’s 2 ml/ kg/%BSA burned Lactated Ringer’s (for Burn) 5000 ml/m2 BSA Burn Saline 1 ml/kg/% BSA burned
–
–
–
–
–
Lactated Ringer’s (maintenance) 2000 ml/m2 TBSA Water (Dextrose) 2000 ml
Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h) Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h) Given over 24 h (1/2 in first 8 h, 1/2 in following 16 h)
(Blood/Dextran/Plasma) 1 ml/ kg/%BSA burned
Brooke
Lactated Ringer’s 1.5 ml/kg/%BSA burned
(Blood/Dextran/Plasma) 0.5 ml/ kg/%BSA burned
Water (Dextrose) 2000 ml
Muir and Barkley
–
‘‘Plasma ration’’ ¼ 1ml per (%BSA burned/kg)/2
–
Given over 24 h, then 1/2 again over second 24 h (not to give more fluid than 50% TBSA burn) Given over 24 h, then 1/2 again over second 24 h (not to give more fluid than 50% TBSA burn) 6 rations given over 36 h (3 rations then 2 rations then 1 ration, over succesive 12 h intervals)
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resuscitation needs to be aggressive to reverse shock, however, it is unclear what the end points of resuscitation should be and at present they are poorly defined. Formulae have been developed over the years, Table 1, to guide initial resuscitation and further fluid is given if necessary to attain normal haemodynamic parameters and a urine output of generally between 0.5 and 1 ml/kg/h. 3.2. Monitoring haemodynamics There has been a tendency to stay away from invasive methods of monitoring cardiac function such as the pulmonary artery catheter, as there is a high risk of complications particularly if left in place for more than 3 days. Although work has demonstrated that survivors of critically illness have greater cardiac output, oxygen delivery and oxygen consumption than non-survivors there is no evidence that treating these patients to try and achieve these supranormal levels improves outcome.31 There may be situations, however, when further haemodynamic monitoring may be advantageous as they may indicate compensated shock and inadequate tissue perfusion, particularly in those who have limited cardiac reserve. The advent, therefore, of less invasive methods of monitoring such as transpulmonary thermodilution, the PiCCO, the lithium dilution cardiac output device (LiDCO) and the oesophageal Doppler may help and with time their roles may become more defined. Transpulmonary thermodilution derives cardiac output (both right and left ventricular output) from a computerised analysis of the arterial thermodilution curve. It is also able to give an estimate for total circulating blood volume and intrathoracic blood volume. In the double indicator technique, an indicator dye is mixed with a cold injectate to improve accuracy. The technique requires central venous access, through which the injectate is given as a bolus, and a special thermistor tipped fibreoptic catheter inserted into a femoral artery (which also acts as an arterial pressure sensor). As most acute burns patients require central venous and arterial pressure monitoring this presents no additional burden in terms of additional intravascular cannulation. Using this double indicator technique of transpulmonary themodilution during burns resuscitation, there has been shown to be a good correlation between the intrathoracic blood volume (ITBV) with both cardiac index and oxygen delivery (DO2).32 Kuntscher et al. also demonstrated that the total circulating blood volume index (TBVI) correlated well with cardiac index and stroke volume during major burns resuscitation,33 implying that restoring the ‘measured’ circulating volume could restore cardiac function. Using this technique, aiming for a intrathoracic blood volume index (ITBVI) above 800 ml/m2 and a cardiac index of >3.5 l/min/m2, results in more aggressive fluid resuscitation, higher urine output and a greater cardiac output at 24 h.32 The double indicator thermodilution technique appears to be a very useful, reproducible34 and accurate35 method of measuring cardiac output and O2 delivery in the burns population, but unfortunately, as of yet, there is no evidence to show that its use is associated with a beneficial effect on outcome. The PiCCO technology is based on the transpulmonary thermodilution technique and provides minimally invasive continuous monitoring of haemodynamic and volumetric parameters. Instead of using a double indicator solution, the PiCCO uses a single thermodilution technique of cold injectate, which is bolused through central venous access and is measured by a special thermistor tipped arterial cannula (femoral, brachial or axillary). As well as providing haemodynamic variables the single thermodilution technique is used to calibrate the arterial pulse contour analysis, which then provides continuous haemodynamic data. The PiCCO has been shown to have a very good correlation with pulmonary artery catheter measurement at normal to low CI, but at a higher CI (>5.5 l/min/m2) the correlation is not as good.36 Unfortunately the
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precision of ITBVI measurements using this technique is poor and hence cannot be used accurately to guide volume resuscitation.37 The LiDCOÔplus is another system which uses an indicator dilution technique for the measurement of cardiac output. A small dose of lithium chloride is given into a central venous cannula or into a peripheral line if central access is not available. Blood is then sampled from an attachment to an existing standard arterial line and the concentration-time curve of the lithium is measured. This information is used to calculate the absolute cardiac output value and to calibrate the pulse contour analysis. The software then analyses the arterial blood pressure trace and calculates the beat to beat ‘real-time’ cardiac output, with recalibration recommended every 8 h there after. There is currently no trial data on the use of LiDCOÔplus in burns patients, although the system has gained popularity due to its ease of use and its ability to use existing vascular access. The system has been studied in animal models although there is currently little work in critically ill patients. The lithium indicator dilution technique appears to have a good correlation with cardiac output measurement compared with the PAC thermodilution method, and variables such as pulse pressure, systolic pressure and stroke volume variations that occur during the respiratory cycle in ventilated patients have been shown to be reliable dynamic markers of ‘fluid responsiveness’.38,39 As with all methods that use pulse contour analysis, the LiDCOÔplus’s accuracy is affected by arterial waveform artefacts such as dampening of the waveform, severe vasoconstriction causing changes in waveform morphology and by irregular pulse rates (especially changes during calibration). Its calibration is also effected by nondepolarising muscle relaxants. Oesphageal Doppler monitoring has also gained some popularity due to its relative ease of use, minimal invasiveness and ability to provide real-time cardiac output data. The technique uses a probe which measures velocity of blood flow in the descending aorta, then using an estimate of aortic cross sectional area various cardiac indices can be calculated. When compared to PAC monitoring during major escharotomy, oesophageal Doppler monitoring has been shown to consistently underestimate cardiac output hence it does not provide accurate absolute values. It is, however, reliably able to show real time changes in volume status.40 3.3. Haemodynamics/biochemistry A large base deficit and elevated lactate levels have been shown to predict mortality in burns patients, particularly in those patients in whom the levels do not return to baseline with resuscitation.41 While a significant base deficit is likely to be related to poor perfusion, there is concern that an elevated lactate may not be a predictor of poor resuscitation but an indicator of burn size. It is unknown whether resuscitation directed at early correction of either base deficit or lactate would lead to less organ dysfunction and an improved outcome, although it is well recognised that persistent unrecognised tissue ischaemia can lead to systemic inflammation and organ failure. 3.4. Fluids Fluids used in initial resuscitation tend to be crystalloid such as Hartmann’s or normal saline and various formulae such as the Parkland formula are used in different burns centres. All provide a guide for resuscitation but fluids need to be adjusted dependant on the patient’s clinical state and may need to be increased if there is an inhalation injury or other coexisting injuries. Under resuscitation and obviously hypovolaemia will occur after large burns if not enough fluid resuscitation is provided but excess fluid will
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worsen tissue oedema. Many units do end up giving more fluids than that which is recommended by formulae and there is therefore concern that over administration of fluids (fluid creep)42 can lead to serious exacerbation of tissue oedema and impaired tissue oxygen utilisation. This oedema can lead to compartment syndromes which may require escharotomy or fasciotomy and may also lead to intra-abdominal hypertension. Intra-abdominal pressures in excess of 30 cm H20 indicate intra-abdominal hypertension (IAH). If left untreated it can lead to acute renal failure, pulmonary dysfunction, reduced cardiac output, splanchnic ischaemia and intracranial hypertension. If IAH is present with a tense abdomen together with either oliguria (despite aggressive fluid resuscitation) or high peak inspiratory pressures (that compromise ventilation) then a diagnosis of abdominal compartment syndrome can be made. Recent reports suggest that the critical volume associated with intra-abdominal hypertension is approximately 300 ml/kg/24 h.43 It has been suggested that the volume of fluid administered following serious burn injuries is increasing as a result of using base deficit rather than urine output as an endpoint, the increased use of opiates and sedatives has also been blamed. It is also possible that transfer to regional units may be a factor, as delayed resuscitation leads to an increase in fluid requirements. It is interesting that a recent paper demonstrated that resuscitation to ITBV end points using the PiCCO rather than to urine output could actually lead to less fluid administration, less oedema formation and less organ dysfunction. This was termed ‘permissive hypovolaemia’.44 3.5. Which fluid The use of colloids in resuscitation remains controversial as studies have not demonstrated any significant improvements in outcome with their use, although less volume may be required for resuscitation leading to less tissue oedema. Some units will give human albumin after 12–24 h if the patient remains under resuscitated,45 however, there was no reduction in multiple organ dysfunction when 5% human albumin was used for resuscitation for adult burn shock.46 In fact a Cochrane review stated recently that as colloids are not associated with an improvement in survival, and as they are more expensive than crystalloids, it is hard to see how their continued use in critically ill patients (including those with burns) can be justified outside the context of randomised, controlled trials.47 Hypertonic saline (7.5% NaCl) may also be of benefit, as in animal models its use has been associated with improved organ perfusion and outcome and it has been shown to enhance host defence to bacterial challenge in mice.48 In adults its use may lead to a reduced total colume, less tissue oedema and a decreased incidence of abdominal compartment syndrome, although this is controversial. There is concern about a potentially increased risk of renal failure.49 It is currently not routinely used. 4. Pharmacological support
Unfortunately use of any vasopressor may lead to progression of the burn wound depth. 4.2. Steroids In septic, burn patients corticosteroids may improve vascular reactivity and allow a reduction in vasopressor dose. There may also be benefit in the presence of impaired adrenocortical function, but it is presently difficult to identify which patients may benefit. It may not be justifiable in view of risks of immune suppression and infection associated with their use. In a recent paper hydrocortisone did not improve survival in patients with septic shock.51 4.3. B-Blockers Once resuscitation is complete following the burn injury, the metabolic rate starts to increase and then reaches a peak up to 2 weeks later. Patients with burns greater than 40% are always catabolic and those with less severe burns will become catabolic with sepsis. This hypermetabolic response typically lasts for 9–12 months post burn and is associated with: severe protein loss increased infection risk impaired wound healing B-Blockers can attenuate this hypermetabolic state but the mechanism of action is unclear. It may be due to enhanced protein synthesis. In a group of 25 children with acute, severe burns of more than 40% TBSA, 12 received oral propranolol to reduce the resting heart rate by 20%. In this group the net muscle-protein balance increased by 82% over baseline values, whilst it fell by 27% in the control group. The fat free mass also significantly decreased in the control group but was mostly unchanged in the protocol group.52 B-Blocker treatment in burned children has been shown to reverse protein catabolism which results in an improved nutritional status.52 It also leads to a lower glucose level and reduced lypolysis53 which leads to less fatty infiltration of the liver. There is also a lower heart rate with a maintained cardiac output due to improved left ventricular filling and stroke volume.54 It has also been suggested that the administration of B-Blockers may improve outcome in adult burns patients.55 Although many burns units use beta blockers to attenuate the hypermetabolic response there is at present no randomised trial looking at outcome in this group of patients. There is also evidence that catecholamines are necessary to fight infections. It has previously been demonstrated that adrenaline enhances platelet neutrophil adhesion in vitro56 and noradrenaline maintains the phagocytic function of macrophages at optimal levels.57 There has therefore been concern that beta blockade may cause a detrimental effect. In a recent study of 245 paediatric burns patients, however, propranolol resulted in an attenuation of hypermetabolism and there was no increase in the incidence of sepsis in the propranolol treated group.58 There was also no significant difference in mortality between the two groups.
4.1. Vasopressors 4.4. Growth hormone Noradrenaline is commonly used to increase blood pressure in septic burns patients, and inotropic agents may be beneficial if there is significant myocardial depression. Determining which patients may benefit may help to improve outcome. There has been recent interest in the use of vasopressin, which was found to be an effective agent that increased blood pressure in septic burns patients who were already receiving noradrenaline.50 Vasopressin had a noradrenaline sparing effect.
Growth hormone is a potent anabolic agent. In a healthy adult population growth hormone has been shown to enhance cardiac performance. In burned children, as well as improving height, weight and lean body mass, long term growth hormone therapy has also been found to significantly improve left ventricular ejection fraction for 12 months after burn injury, although a possible benefit on overall
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cardiac function has yet to be shown.59 Growth hormone, however, has some serious adverse effects. It can lead to hyperglycaemia and has led to an increased mortality in critically ill adult patients.60 This worsened outcome was not seen in paediatric patients.61
24. 25. 26.
5. Conclusion 27.
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