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Table 2. Comparison of studies involving inhaled heparin and N-Acetyl Cystine (NAC) for smoke inhalation

Study	Design	N	Patient selection	Interventions	Outcomes
Desai	Retrospective	90	Pediatric	5000 U aerosolized	Treatment group had signifi-
et al.	Historical		Mean burn size 50%–55%	heparin alternating with	cantly lower reintubation
[26]	Controls		TBSA	3 mL aerosolized 20%	rates,evidence of atelectasis,
			All bronchoscopic-	NAC every 2 hours for	and mortality
			confirmed I I	7 days
			All mechanically
			ventilated
Holt	Retrospective	150	Adults	inhaled 5000U heparin No differences in pneumonia,
et al.	Contemporan-		Mean burn size 27%–32%	with 3 mL 20% NAC	duration of MV, re-intubation,
[27]	eous		TBSA	with albuterol every	LOS, survival, or PaO2/FiO2
	Controls		Only 68% had broncho-	4 hours for 7 days	ratios on days 1, 3, and 7 post
	Unblinded		scope-confirmed I I		burn between treatment and
			physician discretion used		control
			to initiate heparin-NAC
Miller	Retrospective	30	Adults	nebulized 10 000 U	Treatment group showed
et al.	Historical		All mechanically	heparin with 3 ml 20%	significantly better improvement
[20]	Controls		ventilated	nac, and Albuterol every	in LIS, respiratory resistance and
			All with bronchoscope-	4 hours for 7 days	compliance, and hypoxemia
			confirmed I I		compared to controls.

N: number of subjects, I I: inhalation injury, MV: mechanical ventilation, LOS: length of hospital stay, LIS: Lung Injury Score

from heparin-NAC but this study may have been flawed by the fact that only 68% of the study population had a bronchoscopic diagnosis of inhalation injury. Additionally, some of the patients were intubated and mechanically ventilated for as little as one day. Also, the decision to use heparin-NAC was at the attending physician’s discretion.

The available evidence would therefore suggest that for a mechanically ventilated patient with bronchoscopically-confirmed inhalation injury that a one week course of nebulized Heparin (5,000 to 10,000 units) with 3 mL of 20% NAC every four hours with or without the addition of Albuterol may be of benefit. This regimen appears to relatively safe and adverse effects such as NAC-induced bronchospasm or Heparin-induced thrombocytopenia were not reported in any of the studies discussed.

Conventional mechanical ventilation

Introduction

The approach to conventional mechanical ventilation (CMV) for critically ill patients has undergone dramatic change in the past decade. A ventilation strategy that was characterized by the use of liberal

tidal volumes, tolerance of high peak and plateau airway pressures, and the goal of normalization of arterial blood gas values has been replaced by gentler approaches to mechanical ventilation which feature use of lower tidal volumes, limited airway pressures, permissive hypercapnia, and enthusiasm for “open lung” strategies using higher positive and expiratory pressure (PEEP) settings along with lung recruitment maneuvers. While this paradigm shift has largely been adopted in the approach to CMV in the burn patient, three important points should be considered:

Burn patients were either excluded from, or were minimally represented in virtually all of the major trials that have promoted low tidal volume, pressure limited and open lung approaches to CMV

The current approaches to CMV are directed at patients with existing Acute Lung Injury (ALI) andAcuteRespiratoryDistressSyndrome(ARDS). Unlike patients in the Intensive Care Unit who are admitted with some degree of lung dysfunction or injury, the majority of burn patients who are intubated start out their course of mechanical ventilation with relatively normal lungs even in the face of smoke inhalation. Typically, lung dysfunction, pulmonary edema, ALI, and ARDS fre-

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quently develop within days of burn injury and Burn Centre admission. It is the rule rather than the exception that the initial mechanical ventilation is being delivered to uninjured lungs. As such, there has been no research directed at this unique situation and inevitably, ventilation strategies designed for ALI and ARDS are translated to intubated patients with acute burns even though pathology may not yet have developed in the lungs of these patients.

The chest wall mechanics of many burn patients can be vastly different from that of most critically ill patients from whom current CMV strategies have evolved. Specifically, the presence of unyielding eschar, and significant soft-tissue edema on the abdomen and thorax of the burn patient have significant effects on respiratory compliance. Thus airway pressures measured at the ven-

tilator may not be reflective of actual trans-pul- monary pressures in the lung.

This section of the chapter is not intended to give specific formulas or prescriptions for mechanical ventilation of the burn patient. Rather, the intention is to review general concepts and approaches to mechanical ventilation, which are believed to affect respiratory outcomes bearing in mind the above points, which draw attention to the fact that most of these principles have been developed in patients without burns but have inevitably been adopted by burn clinicians and translated to the burn patient.

Pathophysiological principles

All of the general principles of current CMV strategies which will be discussed below have evolved from an improved understanding of the pathology of ALI and ARDS, and the recognition that mechanical ventilation may itself be harmful to the lungs and may directly cause new, or worsen existing ALI and ARDS. This process is referred to as ventilatory induced lung injury (VILI) [28, 29]. Specifically, ventilation with large tidal volumes and high peak airway pressures causes injury through excessive stretch of the alveoli (volutrauma), while inadequate and inspiratory pressures allow shear injury to occur from repetitive alveolar collapse and then re-opening (atelectrauma). These mechanical injuries then cause

inflammation which further injures the lung (biotrauma) [28, 29].

It is essential to appreciate that heterogeneity is the defining feature of the lungs in patients with ALI and ARDS. Computed tomography studies have been seminal in understanding the herterogeneous pathology of ARDS [30]. Some areas of the lung (usually the non-dependent regions) may be relatively unaffected while other areas (usually the dependent areas posterior to the heart and mediastinum) show atelectasis and consolidation. Furthermore, some of the affected alveoli show predominantly consolidation, while others show predominantly atelectasis, even within the same lung. Hence, some parts of the lung do not receive ventilation because they are consolidated and less compliant so that mechanical ventilation ends up being delivered to a much smaller than normal volume of less affected, or even normal lung. This has been referred to as the “baby lung” concept[31] which refers to the idea that during ARDS only a small functioning baby-sized lung is being ventilated inside a fully grown adult. Thus, if traditional adult-sized airway pressures and tidal volumes are used, these are delivered only to a small portion of the lung thus causing barotrauma or volutrauma.

To complicate matter further, some forms of ARDS feature “loose” or more recruitable lung (e.g. from inflammatory edema) whereas other forms feature “sticky” non-recruitable lung (e.g. consolidative pneumonia) [32–34]. For example, it is conceivable (but unknown at present) whether ARDS after smoke inhalation may feature a predominance of “sticky” non-recruitable alveoli, rather than “loose” more recruitable alveoli.

Low tidal volume and limited plateau pressure approaches

The well-known large multi-centre study by the acute respiratory distress syndrome of the National Heart Lung, and Blood Institute (ARDS Net) in 2000 found that a traditional approach using tidal volumes of 12 mL/kg predicted body weight (PBW) and plateau pressures up to 50 cmH2O was associated with significantly higher mortality than a CMV strategy using a tidal volume of 6 mL/kg PBW and plateau pressures limited to less than 30 cmH2O [35]. The other important trials that have examined the use of low

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Table 3. Comparison of randomized prospective studies using low tidal volume (Vt) and limited plateau Pressures (Pplat) strategies for mechanical ventilation of patients with ARDS

Study	N	Target Vt (mL/kg) and		Actual Vt (mL/kg) and	%	P
		Pplat (cm H2O)		Pplat (cm H2O)	Mortality	value
ARDS Net et al. [35]	861	6 vs 12 and 30 vs 50		6.2 vs 11.8 and 25 vs 33	31 vs 40#	0.007
Amato et al. [36]	53	6 vs 12 and > 20 vs no limit		384 mL vs 768 mL * and 30 vs 37	38 vs 71§	0.001
Brochard et al. [37]	116	6–10 vs 10–15 and 25–30 vs 60		7.1 vs 10.3 and 26 vs 32	47 vs 38¶	0.38
Stewart et al. [38]	120	8 vs 10	–15 and 30 vs 50	7.0 vs 10.7 and 22 vs 27	50 vs 47†	0.72
Brower et al. [39]	52	8 vs 10	–12 and 30 vs 45–55	7.3 vs 10.2 and 25 vs 31	50 vs 46†	0.61

* Vt was reported in mL, # mortality at hospital discharge or 180 days, § mortality at 28 days, ¶ mortality at 60 days, † mortality in-hospital

tidal volumes and limited plateau pressure strategies are summarized in Table 3 [35–39]. The three negative trials may not have recognized a mortality difference because of the relatively narrow differences in actual tidal volumes and plateau pressures between the treatment and control arms [37–39].

In general, based largely upon the ARDSNet recommendations for ALI and ARDS, mechanical ventilation in burn patients is now similarly initiated with an initial tidal volume of 6–8 mL/kg PBW and a goal of maintaining plateau pressures less than 30 cm H20and peak inspiratory pressures less than 35 cmH20. This approachassumesrelativelynormalthoracoabdominal compliance. In a massively edematous burn patient with chest wall or abdominal burns it may be necessary to use larger tidal volumes (8–10 mL/kg) to achieve adequate alveolar patency while accepting higher plateau pressures (up to 35 cmH2O).

Permissive hypercapnia

Aggressive pursuit of a normalized PaCO2 and pH is no longer the goal of current CMV strategies [40, 41]. Low tidal volume strategies result in lower minute ventilation which can cause hypercapnia. While a large acute elevation in the PaCO2 may be associated with adverse effects (vasodilation, decrease cardiac output, increased intracranial pressure), the effects of more prolonged but less severe hypercapnia appear to be better tolerated but data is lacking to fully support this notion. Ideal levels of PaCO2 and pH are not identified. It should be noted that the ARDSNet investigators utilized increases in respiratory rate, bicarbonate infusions and increased tidal volumes

to deal with acidosis. The use of bicarbonate infusions as a buffer remains controversial. Although pH may be corrected with bicarbonate, intra-cellular pH may actually drop since CO2 produced when bicarbonate binds with metabolic acids may accumulate within cells, resulting in intra-cellular acidosis [40]. General guidelines would include maintaining pH between 7.25 and 7.45 and the PaCO2 between 35 and 55, although higher PaCO2 may be tolerated if the pH is above 7.25.

The open-lung approach

As noted, portions of the lung in ALI and ARDS are characterized by collapse of small airways and alveoli. During positive pressure ventilation these alveoli open during inflation but will re-collapse if end expiratory pressures are inadequate. The repetitive opening and collapse causes shear injury to the alveolus (atelectrauma), and is detrimental. It is therefore highly desirable to open alveoli and keep them open, not only to avoid shear injury but also to improve oxygenation. This concept is referred to as an “open lung” approach. The two main techniques involved in this strategy are the use of positive and expiratory pressure (PEEP) and lung recruitment maneuvers. However, despite a solid physiological basis, the optimal use of PEEP and lung recruitment maneuvers remain mired in controversy.

PEEP

The ideal level of PEEP and the best method for determining that level are unknown. If PEEP is too low,

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atelectasis is not reversed. Unnecessarily high PEEP may cause stretch injury to the aerated alveoli as well as haemodynamic instability, barotrauma, and may worsen ventilation perfusion matching [40–42].

In the limited tidal volume and plateau pressure study by Amato, et al. [36] PEEP was set at a level just above the lower inflection point on the pressure volume curve which in theory is the point above which recruitable alveoli are kept open at the end of expiration. However, this approach may not be practical and the derived pressure volume curve may not accurately represent regional differences across all regions of the lung because of the heterogeneity of the ARDS process. Nevertheless, PEEP levels as high as 24 cmH2O were used in the high PEEP/low tidal volume arm of this study and were associated with significantly lower mortality rates.

Another approach which was used in the ARDS Net study of low volume and pressure was to arbitrarily link certain PEEP and FIO2 combinations to achieve adequate oxygenation. In general, PEEP levels between 5 and 20 cmH2O probably provide an acceptable balance between the adverse effects of inadequate and expiratory pressure and the risks of excessive end-expiratory pressure. Again, however, optimal PEEP levels remain unknown at this point.

Four large randomized multi-centre prospective studies have tried to determine whether there is a benefit to use of higher PEEP vs. lower PEEP settings (Table 4) [43–46]. The ALVEOLI Trial conducted by the ARDS Net investigators [43] compared a high PEEP (mean setting 13 cmH2O) to low PEEP (mean setting 8 cmH2O) among 549 patients with ALI and ARDS who were all ventilated with a tidal volume goal of 6 mL/kg PBW and a plateau pressure limit of

30 cmH2O, and found that although the high PEEP group and significantly higher PaO2/FiO2 ratios, there were no significant differences in ventilator-free days or survival.

In the ARIES trial conducted by Villar, et al. [44] ARDS patients were randomized to either low PEEP (PEEP above 5 cmH2O) plus higher tidal volume (9–11 mL/kg PBW) or, to high PEEP (PEEP set above lower inflection point on the static TV curve) plus lower tidal volume (5–8 mL/kg PBW). The high PEEP/lower tidal volume group had significantly greater ventilator-free days and ICU and hospital survival. However, any specific benefit of higher PEEP cannot be determined from this study because it was combined with a lower tidal volume approach compared to that in the low PEEP group.

More recently the EXPRESS trail [45] randomized patients with ALI and ARDS using a tidal volume of 6 mL/kg to either moderate PEEP (5–9 cmH2O) or to higher PEEP which was set to achieve a plateau pressure up to 30 cmH2O. Although the higher PEEP group had significantly superior oxygenation and a greater number of ventilator-free days, overall survival was not significantly different than in the low PEEP group.

Finally, in the LOVS study [46] of 983 patients with ALI and ARDS whose PaO2/FiO2 ratio was less than 250 were randomized to a target tidal volume of 6 mL/kg, no recruitment maneuvers, and PEEP set to keep the plateau pressure less than 30 (low PEEP group) or to a tidal volume of 6 mL/kg, lung recruitment maneuvers, and PEEP set to keep the plateau pressure less than 40 cmH2O (high PEEP group). Overall, in-hospital survival did not differ between the groups but the high PEEP group had a significantly lower mortality rate secondary to refractory hypoxemia and a significantly lower rate of use of

Table 4. Comparison of randomized prospective studies using lower positive end expiratory pressure (PEEP) vs higher PEEP for acute lung injury and acute respiratory distress syndrome

Study	N	Actual Vt (mL/kg) and	Actual Plateau Pressure (cm H2O)	%	P
		PEEP (cm H2O)*		Mortality	value
ARDS Net [43]	549	6.1 vs 5.8 and 8.5 vs 12.9	24 vs 26	25 vs 28 #	0.48
Villar et al. [44]	103	10 vs 7.1 and 8.7 vs 11.2	33 vs 28	56 vs 34 #	0.04
Mercat et al. [45]	767	6.2 vs 6.2 and 6.7 vs 13.4	21 vs 27	39 vs 35 ¶	0.30
Meade et al. [46]	983	6.7 vs 6.9 and 8.8 vs 11.8	25 vs 29	40 vs 36 #	0.19

Vt: tidal volume, * on day three, # in-hospital mortality, ¶ 60-day mortality

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