Given that a cornerstone of critical care is the recognition of at-risk patients, the implementation of preventive and therapeutic strategies early in the course of critical illness is crucial to patient outcome.⁴ Similarly, potentially promising, novel mechanistic interventions are not likely to have a meaningful impact unless applied early in the course of a critical illness before irreversible changes occur.

To review the challenges and opportunities related to the paradigm shift from treatment to prevention of multiple-organ dysfunction, in this chapter we focus on ARDS. The same concepts discussed here are likely to apply to acute kidney injury, disseminated intravascular coagulation, and other syndromes of critical illness.

ARDS and the Multiple-Hit Hypothesis

The concept of lung injury was brought to physicians’ attention during World War I, with subsequent description of a trauma-related syndrome referred to as “wet lung” or “shock lung.”⁵ During the 1960s, a case series of 12 patients with respiratory failure was published, and the term acute respiratory distress syndrome (ARDS) was adopted for the syndrome.⁶ As described in the preceding chapter, the original American-European Consensus Criteria definition⁷ has been recently updated to the new Berlin definitions of mild, moderate, and severe ARDS based on acute onset, bilateral diffuse infiltrates on radiograph, hypoxemia, and noncardiogenic pulmonary edema.⁸

Despite the advances in knowledge of the pathophysiological process of ARDS over the past 40 years, ARDS is still associated with a hospital mortality of 25% to 40%.^9-11 Over this time period, the great majority of the research done in ARDS has been limited to improvements in supportive treatment of the disease such as mechanical ventilation strategies, fluid management, sedation, and rehabilitation. Once the syndrome is fully established, most of the treatment options for ARDS have had little effect on decreasing the length of mechanical ventilation, ICU or hospital length of stay, and mortality rate.¹²

The multiple-hit hypothesis was initially described for cancer development and is defined as a result of accumulated mutations (multiple hits) to the DNA of a living cell.^13,14 Researchers have applied a similar framework to many other diseases by outlining the baseline risk factors, which primarily predispose the patient to disease (first hits), and the risk modifiers, which increase or decrease the risk of the disease (second hits).

As a broad concept, there are 2 fundamental steps to manage patients with ARDS¹⁵:

1. Identify the underlying risk factor (first hit) and reverse the inflammatory cause as soon as possible.
   
2. Avoid iatrogenic harm (second hits) and introduction of proinflammatory reactions that will maintain the lesion.

A priori knowledge about the first and second hits is essential to implementing future preventive strategies and incorporating them into healthcare delivery algorithms.

Toward the Prevention of ARDS and Other Organ Failures

Early Identification of At-Risk Patients

A population-based cohort study showed that in more than 80% of ARDS cases followed, patients had a healthcare contact before admission to the ICU.¹⁶ In other words, more than 80% of the ARDS cases potentially could have been prevented by early identification of at-risk patients and implementation of appropriate interventions early in the course of the disease.

Since previous studies have almost exclusively focused on patients who were already admitted to the ICU,^17-21 the question of why some patients with a risk factor do and others do not develop ARDS remains under investigation.

In a study by Trillo-Alvarez et al,²² only 1% of patients admitted to the hospital without any risk factor eventually developed ARDS. Therefore, clinical risk factors proven to be associated with ARDS may help identify at-risk patients early or at the time of a first healthcare contact and may be used to establish an adequate prevention strategy.

According to the results of 2 prospective studies, clinical predisposition for ARDS was attributed to several conditions, including sepsis, aspiration, multiple trauma, and transfusions. These conditions were found to be associated with ARDS with an incidence of 38%-43%, 30%, 25%, and 25%-40% respectively.^23,24

The Lung Injury Prediction Score was recently developed to identify at-risk patients without current evidence of ARDS.²² This model subsequently was validated by a multicenter observational study arranged via the US Critical Illness and Injuries Trials (USCIIT) Group.²⁵ In this study, a score of 4 or higher was found to be predictive of ARDS development with a 69% sensitivity and a 78% specificity (area under the curve, 0.8). The risk factors shock (17%), aspiration (16.5%), and high-risk surgery (16%) were most frequently associated with development of ARDS.

Standardizing Best Practices

Simple interventions such as early and appropriate antimicrobial treatment, early recognition and treatment of cardiorespiratory failure, low tidal volume mechanical ventilation, deep vein thrombosis and stress ulcer prophylaxis, and standardized weaning, sedation, and physical therapy protocols require little specialized equipment but are crucial to successful outcome of critically ill patients.

Early Recognition and Treatment of Shock and Infection

Rapid restoration of effective circulating volume in patients with shock and early, appropriate use of antimicrobials in patients with evidence of infection are associated with increased survival and may constitute essential strategies for preventing the development of ARDS and other organ failures.^26,27 In an observational cohort study, shock and infection were found to be associated with an odds ratio of 3.55 for the development of ARDS.²⁶

Conservative Fluid Management Strategy

In a prospective, randomized trial, the use of a conservative fluid management strategy in ARDS was found to be associated with reduced ventilator and ICU stays.²⁸ A subsequent retrospective review of 212 patients with ARDS complicating septic shock suggested that the combination of adequate initial fluid resuscitation and a conservative late fluid management strategy was associated with reduced mortality in ARDS.²⁹ In this study, survival was greatest in patients who achieved adequate initial fluid resuscitation (an initial fluid bolus >20 mL/kg prior to vasopressor initiation and achievement of a central venous pressure >8 mm Hg within 6 hours after vasopressor initiation) and conservative late fluid management strategy (even-to-negative fluid balance on at least 2 consecutive days during the first 7 days after septic shock onset). Although causality was not clearly demonstrated, a clear signal to manage the need for “ebb and flow”³⁰ in volume management was suggested. In addition, the potential impact of early volume management on longer term functional and neuropsychological quality of life outcomes requires further study.³¹

Low Tidal Volume Strategy

Strong evidence suggests that ARDS patients ventilated with a low tidal volume strategy (6-8 mL/kg predicted body weight) have a significantly improved outcome.³² Furthermore, other reports suggest an association between the initial tidal volume and the development of ARDS in patients intubated for reasons other than ARDS.³³ Therefore, ventilator-associated lung injury may be an important and preventable cause of this syndrome. Since height and gender are better predictors of lung size than is the actual weight of the patient, these 2 parameters should be considered in ventilator settings.³⁴ In our practice, we have shown that the adjustment of initial tidal volume according to a simple chart of predicted body weight calculated by gender and height could limit patients’ exposure to injurious tidal volume and their subsequent mortality.³⁵

Transfusion

Transfusion is another risk factor for the development of ARDS in critically ill patients.³⁶ In clinical practice, blood products often are not transfused according to evidence-based guidelines. The prevention of liberal use of blood products has been shown to significantly decrease the incidence of transfusion-related acute lung injury (TRALI).³⁷

It is known that transfusions of plasma-rich blood products, fresh frozen plasma, and platelets are associated with greater risk of developing ARDS than is transfusion of red blood cells.¹⁸ Alloimmunized donors carry an additional risk for the development of TRALI.³⁶ A history of prior pregnancy and previous transfusion was found to be highly correlated with human leukocyte antigen (HLA) alloimmunization, leading to the suggestion that testing only donors with a history of pregnancy or transfusion can serve as a prevention strategy for the development of TRALI.³⁸ In our clinical practice, shifting the procurement protocol to male-only donors for plasma and platelets led to a sustained decrease in TRALI.³⁹

Prevention of Aspiration

Aspiration is recognized as a risk factor in 11% of ARDS cases, with an associated mortality of 44%.⁴⁰ Unfortunately, there is a concern that the true incidence and subsequent mortality of aspiration may be underestimated, since the diagnosis of aspiration is subjective and usually relies on a “witnessed aspiration event,” which suggests that many aspiration events that lead to ARDS are overlooked.⁴¹ Because aspiration can occur without consequence, more commonly in some chronic conditions (eg, gastroesophageal reflux disease) rather than acutely in the critically ill (eg, vomiting a large amount of gastric content), the precise mechanisms of injury are not clearly understood. Elevating the head of the bed could be a simple but effective prevention strategy for aspiration, particularly in mechanically ventilated patients.

Prevention of Ventilator-Associated Pneumonia

Prevention and management of ventilator-associated pneumonia (VAP) are among the pillars of a daily plan of care in the ICU. Ventilator-associated pneumonia can be seen as a complication of ARDS, but it is also an important risk factor for the development of ARDS. The “ventilator bundle,” which is being promoted to prevent VAP and related complications in mechanically ventilated patients, consists of 4 key components: elevation of the head of the bed to 30° to 45°, daily sedation vacation and daily assessment of readiness to extubate, peptic ulcer disease prophylaxis, and deep venous thrombosis prophylaxis.⁴² In a study of a 61-hospital collaborative, compliance with the full bundle was reported to be more than 95% in 21 ICUs and was associated with a 59% subsequent decrease in VAP rates.⁴³

Additional data suggest that the use of chlorhexidine for oral care and hygiene, selective digestive decontamination, and specialized endotracheal tubes (continuous aspiration of subglottic secretions, silver-coated tubes) should be considered for more specific VAP prevention.⁴⁴

Li at al⁹ recently reported a dramatic decrease in the incidence of hospital-acquired ARDS in Olmsted County, Minnesota, that was temporarily associated with the sequential implementation of quality improvement interventions specifically targeting the above-mentioned second-hit ARDS modifiers (Figures 7-2 and 7-3).

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