Do inhaled vasodilators in ARDS make a difference?

19 Do Inhaled Vasodilators in ARDS Make a Difference? Francois Lamontagne, Paige Guyatt, and Maureen O. Meade

INTRODUCTION Inhaled vasodilators have a compelling physiologic rationale in the management of critically ill patients with acute respiratory distress syndrome (ARDS). A 25-year accumulation of rigorous research has helped to clarify their role in this setting, which is significantly more limited than original reports suggested.

PHYSIOLOGIC RATIONALE Lung imaging studies in patients with ARDS show alveoli that are poorly aerated due to exudative edema, hyaline membranes, and microatelectasis that are not homogeneously distributed throughout the lung parenchyma. Instead, patchy areas of lung tissue are relatively preserved and remain compliant, allowing them to receive disproportionately large fractions of the minute ventilation.1,2 The more diseased lung regions, located predominantly in the dependent areas of the lungs, may be poorly ventilated and yet receive much of the right ventricular cardiac output, resulting in a significant mismatch. Heart–lung interactions can occasionally contribute to the pathology of ARDS. Laboratory research shows that hypoxiainduced vasoconstriction can result in pulmonary hypertension.3,4 This is compounded by the dysregulation of constricting and dilating mediators, which can further increase pulmonary vascular resistance.5 In severe ARDS, these effects may lead to right ventricular failure, a plausible independent predictor for death.6 Vasodilators delivered through the ventilator will preferentially reach the relatively more compliant lung regions, which are also most amenable to participate in gas exchange. Theoretically, the selective vasodilatation of vessels perfusing aerated lung tissue would redistribute blood flow from poorly ventilated regions, reducing the shunt fraction and at the same time correcting pulmonary hypertension. Improved oxygenation would reduce the mortality risk that is directly attributable to respiratory and right ventricular failure, while quicker resolution of ARDS would reduce the complications and morbidities associated with prolonged mechanical ventilation.7 Unfortunately these are not the effects observed in randomized clinical trials. The following discussion will focus mainly on inhaled nitric oxide (NO), which is by far the most extensively studied

inhaled vasodilator in the context of ARDS. Additional data are available for nebulized prostaglandins, specifically epoprostenol, alprostadil, and dinoprostone.

NITRIC OXIDE In 1993, Rossaint et al. completed a prospective cohort study of 10 adults with ARDS and observed that inhaled NO, in comparison to intravenous prostacyclin, improved oxygenation.8 This report supported the potential benefit of selective pulmonary vasodilatation. Other preclinical and clinical observational studies supported this effect of inhaled NO on arterial oxygenation.9–11 Added to further laboratory investigations finding additional benefits of NO on platelet and leukocyte function,12 these results inspired the conduct of several randomized clinical trials and systematic reviews. Systematic reviews have consistently challenged the potential for inhaled NO to improve survival in adult ARDS.13–16 Among the included randomized trials, study populations varied. Most included adults with moderate to severe ARDS; however, some included children,17–19 less severe ARDS,20,21 or patients with a demonstrated favorable physiologic response to inhaled NO.22 Protocols for the dose and duration of therapy also varied from 1 to 80 ppm and from less than 1 day to 28 days, respectively. One trial was a dose-finding study.22 Lastly, efforts to minimize bias ranged across the studies: ten had concealed allocation,17,18,20–28 five studies blinded caregivers,18,21,23,26,28 and six reported on the use of alternative experimental therapies for ARDS.20,21,23–25,29 Despite the nuances of study populations, therapeutic protocols, and methodologic rigor, the results related to mortality were strikingly consistent. The relative similarity of patients, methods, and the results supports the decision to statistically aggregate results for this outcome. With or without statistical pooling, a visual review of the metaanalytical results provides a strong impression (Fig. 19.1). The aggregate results further suggest that inhaled NO does not improve survival despite a demonstration of improved oxygenation. The trends are more in keeping with increased mortality (relative risk 1.06; 95% CI 0.93 to 1.22).14 Furthermore, the pooled results consistently suggest that inhaled NO is not beneficial in terms of ventilator-free days (mean difference –0.57; 95% CI –1.82 to 0.69).14 137

138

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ARDS

Analysis I.I Comparison I Mortality: iNO versus control group, outcome I Longest follow-up mortality (complete case analysis): iNO versus control

Review: Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults Comparison: I Mortality: iNO versus control group Outcome: I Longest follow up mortality (complete case analysis): iNO versus control

Weight

Risk ratio M-H, Fixed, 95% Cl

7/15

3.0%

1.14 [0.56, 2.35]

1/12

2/12

0.9%

0.50 [0.05, 4.81]

Dellinger 1998

35/120

17/57

9.8%

0.98 [0.60, 1.59]

Dobyns 1999

22/53

24/55

10.1%

0.95 [0.61, 1.47]

Gerbach 2003

3/20

4/20

1.7%

0.75 [0.19, 2.93]

Ibrahim 2007

9/15

8/15

3.4%

1.13 [0.60, 2.11]

Lundin 1999

48/93

38/87

16.8%

1.18 [0.87, 1.61]

Mehta 2001

4/8

3/6

1.5%

1.00 [0.35, 2.88]

11/20

9/20

3.8%

1.22 [0.65, 2.29]

8/17

2/6

1.3%

1.41 [0.41, 4.87]

53/98

53/105

21.9%

1.07 [0.82, 1.39]

0/9

0/10

Taylor 2004

54/165

53/167

22.5%

1.03 [0.75, 1.41]

Troncy 1998

9/15

8/15

3.4%

1.13 [0.60, 2.11]

Total (95% Cl)

660

590

100.0%

1.06 [0.93, 1.22]

Study or subgroup

iNO n/N

Control n/N

Cuthbertson 2000

8/15

Day 1997

Michael 1998 Park 2003 Payen 1999 Schwebel 1997

Risk ratio M-H, Fixed, 95% Cl

Not estimable

Total events: 265 (iNO), 228 (Control) Heterogencity: Chi2 = 203, df = 12 (P = 1.00); I3 = 0.0% Test for overall effect: Z = 0.90 (P = .37) Test for subgroup differences: Not applicable 0.01

0.1

1

Favors experimental

10

100

Favors control

Fig. 19.1  ​Inhaled nitric oxide (iNO) for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults (Review). (Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The systematic reviews also consistently suggest a statistically significant increase in the risk of renal dysfunction with inhaled NO therapy in the four studies that evaluated this outcome (relative risk 1.59; 95% CI 1.17 to 2.16).14–16 One unblinded and three blinded trials observed this effect.21–23,26 A subsequent propensity-matched cohort study of 547 patients confirmed this finding, reporting that inhaled NO was associated with a 59% increase in the use of renal replacement therapy in ARDS.27 The generalizability of these results to clinical practice is high. The studies included patients across the spectrum of

ARDS that clinicians commonly considered (prior to the publication of these studies) for inhaled NO therapy. Moreover, the treatment effects were strikingly similar across studies, notwithstanding the variations in populations, drug administration protocols, and methodologic quality. In parallel to these systematic reviews, data on the longterm quality of life outcomes and costs of inhaled NO have emerged. Using the dataset of a previously published trial of inhaled NO in ARDS,21 Angus et al.30 reported a cost-effectiveness analysis suggesting that inhaled NO did not modify long-term outcomes nor post-hospital discharge

CHAPTER 19

costs. In contrast, a separate retrospective analysis of the same dataset observed positive effects of inhaled NO on the longterm pulmonary function of ARDS survivors who had parti­ cipated in the trial.31 At 6 months, the 51 survivors treated with inhaled NO (vs. 41 who were not treated with inhaled NO) had a greater mean (standard deviation [SD]) (1) total lung capacity (TLC: 5.54 [1.42] vs. 4.81 [1.0], P 5 .026); (2) percentage of predicted forced expiratory volume in 1 second (FEV1: 80.2 [21.2] vs. 69.5 [29.0], P 5 .042); (3) percentage of predicted forced vital capacity (FVC: 83.8 [19.4] vs. 69.8 [27.4], P 5 .02); (4) percentage of predicted FEV1/FVC (96.1 [13.8] vs. 87.9 [19.8], P 5 .03); and (5) percentage of predicted total lung capacity (93.3 [18.2] vs. 76.1 [21.8], P , .001). Medjo et al.32 reported on a prospective observational study of inhaled NO in 16 children with ARDS who were compared to historical controls. Although oxygenation improved for up to 4 hours with inhaled NO, values had returned to baseline 24 hours after the onset of therapy and survival was not improved. In summary, current clinical trials do not support a role for inhaled NO in the routine management of patients with acute lung injury and ARDS. In fact, meta-analyses suggest this approach to patient care is more likely to cause harm.13–16

PROSTAGLANDINS Bearing the same physiologic rationale as inhaled NO in ARDS, three vasodilating prostaglandin molecules are a focus of interest in ARDS research: epoprostenol (also known as prostacyclin, or PGI2), alprostadil (PGE1), and dinoprostone (PGE2). Additionally, epoprostenol blocks platelet aggregation and neutrophil migration and dinoprostone has anti-inflammatory properties. For these reasons, many investigators have hypothesized that nebulized prostaglandins would serve as selective vasodilators and, therefore, useful adjuncts in the context of ARDS. The body of literature evaluating a role for inhaled prostaglandins in the management of patients with ARDS is limited. Dahlem et al.33 reported that among 14 children with ARDS randomized to nebulized prostacyclin or placebo, oxygenation did improve with prostacyclin (median change in oxygen index –2.5, interquartile range –5.8 to –0.2) but mortality was unchanged. Other uncontrolled trials led to similar results. In a dose-finding study, Van Heerden et al.34 treated 9 adult patients suffering from ARDS with inhaled prostacyclin. PaO2/ FiO2 increased, but prostacyclin had no effect on hemodynamic variables or on platelet function. Sawheny et al.35 treated 20 patients with ARDS and elevated pulmonary arterial pressures with prostacyclin. The mean PaO2/FiO2 ratio increased from 177 (SD 60) to 213 (SD 67) but PaCO2, peak and plateau airway pressures, systemic blood pressure, and heart rate did not change significantly. More recently, Kallett and colleagues36 determined that 60% of patients experience improved oxygenation with inhaled prostacyclin. Using a different prostaglandin, Meyer et al.37 treated 15 adult patients with acute lung injury with inhaled dinoprostone. The mean PaO2/FiO2 ratio increased from 105 (standard error [SE] 9) to 160 (SE 17) (P , .05) after 4 hours and to 189 (SE 25) (P , .05) after 24 hours.

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In contrast, Camamo et al.38 reviewed the charts of 27 patients treated with epoprostenol or alprostadil for a primary or secondary diagnosis of ARDS and found no statistically significant improvement in oxygenation. Similarly, Domenighetti et al.,39 in a prospective uncontrolled trial of nebulized prostacyclin to 15 consecutive patients with ARDS and severe hypoxemia, found no improvement in oxygenation.

COMPARISONS OF INHALED NITRIC OXIDE AND PROSTAGLANDIN In contrast to the original 10-patient study reported by Rossaint and colleagues,40,41 direct comparisons of nebulized epoprostenol and inhaled NO have consistently observed similar clinical effects between the two agents. Various groups titrated doses of both agents sequentially and observed nearly identical effects on pulmonary arterial pressure and distribution of blood flow. Torbic and colleagues42 retrospectively compared vasodilator effects in 105 patients, and found no difference in the change in PaO2/FiO2, duration of mechanical ventilation, or intensive care unit or hospital lengths of stay. They did observe that inhaled NO was 4.5 to 17 times more expensive than nebulized epoprostenol. More recently, Ammar and colleagues43 compared inhaled nitric oxide and epoprostenol in a retrospective, propensity-matched cohort study of 102 patients with ARDS and found no difference in oxygenation effects, ventilator free days, or survival.

RECONCILING THE RATIONALE WITH CLINICAL RESEARCH FINDINGS This discordance between physiologic outcomes and survival is not without precedent in critical care. In a landmark study of low tidal volume ventilation conducted by the ARDS Network, patients ventilated with low tidal volumes had lower oxygen levels but an increased survival rate when compared with those patients receiving traditionally larger tidal volumes.44 A disconnect between effects of inhaled NO on physiologic outcomes and survival fits with the understanding that ARDS patients seldom die of respiratory failure.45 Yet for the minority of patients with profound and refractory hypoxemia threatening immediate survival the question remains unanswered. There are insufficient research data in this specific at-risk subgroup to conclude that inhaled NO is, on balance, more likely to benefit or to harm. There are a number of plausible explanations for the lack of benefit of inhaled NO and, probably, prostaglandins in most patients with ARDS. It is conceivable that the purported physiologic benefits are offset by relatively hidden deleterious effects on other organ systems. Contrary to common belief, recent experiments have shown that inhaled NO does not act strictly within the pulmonary vasculature: rather. it reacts with various molecules to produce nitrosothiol compounds that share many properties of NO donors but have longer half-lives.46–49 This evidence, in keeping with the unexpected association between inhaled NO administration and renal dysfunction, suggests that the pharmacodynamic effects of

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inhaled NO are probably more complex than originally understood. The data on inhaled prostaglandins are less clear, but the same principles may apply.

SUMMARY The use of inhaled vasodilators appeals to our current understanding of ARDS physiopathology. Caregivers expect that by limiting ventilation–perfusion mismatch, these medications will improve survival. Also there are hypotheses related to pleiotropic effects on leukocyte migration, platelet adhesion, and overall inflammation. Inhaled vasodilator therapies, therefore, have been subjected to wide and rapid dissemination.50 A careful examination of randomized trials, however, reveals disappointing results. In the case of NO, where the overall trend is indicative of harm, there are now sufficient data—in quantity and quality—to suggest that inhaled NO should not be used in the routine management of patients with ARDS, as noted in current clinical practice guidelines.51 Whether or not this therapy can make a difference in the setting of severe, life-threatening refractory hypoxemia is uncertain but any potential benefit should be weighed against the risk for extrapulmonary side effects such as renal failure, and its high cost. Less data are available to address the potential role for nebulized prostaglandin therapy, but the learnings from NO research warrant caution.

AUTHORS’ RECOMMENDATIONS • There is a compelling physiologic rationale behind the use of inhaled pulmonary vasodilators in the treatment of hypoxemia and right heart failure, secondary to hypoxic pulmonary vasoconstriction. • Studies of inhaled nitric oxide (NO) and inhaled prostaglandins demonstrate improved oxygenation. • There is no evidence that inhaled vasodilators reduce mortality. • In the case of inhaled NO, the trend is towards worse, rather than improved outcomes. This includes an increase in the incidence of acute kidney injury. • Inhaled NO is not cost-effective. Inhaled prostaglandins are significantly less expensive, but clinical efficacy has not been demonstrated. • Inhaled vasodilators may have some value as “rescue therapy” in extreme situations, but this is not currently supported by data.

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37. Meyer J, Theilmeier G, Van Aken H, et al. Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure. Anesth Analg. 1998;86:753-758. 38. Camamo JM, McCoy RH, Erstad BL. Retrospective evaluation of inhaled prostaglandins in patients with acute respiratory distress syndrome. Pharmacotherapy. 2005;25:184-190. 39. Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response. Crit Care Med. 2001;29:57-62. 40. Eichelbrönner O, Reinelt H, Wiedeck H, et al. Aerosolized prostacyclin and inhaled nitric oxide in septic shock—different effects on splanchnic oxygenation? Intensive Care Med. 1996; 22:880-887. 41. Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153:991-996. 42. Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S, Weinhouse G. Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients. J Crit Care. 2013;28:844-848. 43. Ammar MA, Bauer SR, Bass SN, Sasidhar M, Mullin R, Lam SW. Noninferiority of inhaled epoprostenol to inhaled nitric oxide for the treatment of ARDS. Ann Pharmacother. 2015;49:1105-1112. 44. The Acute Respiratory Distress Syndrome Network; Brower RG, Matthay MA, et al.. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308. 45. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1985;132:485-489. 46. Fox-Robichaud A, Payne D, Hasan SU, et al. Inhaled NO as a viable antiadehesive therapy for ischemia/reperfusion injury of distal microvascular beds. J Clin Invest. 1998;101:2497-2505. 47. Keaney Jr JF, Simon DI, Stamler JS, et al. NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest. 1993;91:1582-1589. 48. Kubes P, Payne D, Grisham MB, Jourd-Heuil D, Fox-Robichaud A. Inhaled NO impacts vascular but not extravascular compartments in postischemic peripheral organs. Am J Physiol. 1999; 277:H676-H682. 49. Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature. 1996;380:221-226. 50. Beloucif S, Payen D. A European survey of the use of inhaled nitric oxide in the ICU. Working Group on Inhaled NO in the ICU of the European Society of Intensive Care Medicine. Intensive Care Med. 1998;24:864-877. 51. Claesson J, Freundlich M, Gunnarsson I, et al. Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome. Acta Anaesthesiol Scand. 2016;60:697-709.

e1 Abstract: Inhaled vasodilators have a compelling physiologic rationale in the management of critically ill patients with acute respiratory distress syndrome (ARDS). Accordingly, early preclinical and clinical observational studies suggested that inhaled nitric oxide (NO) could substantially improve arterial oxygenation. Other laboratory investigations reported additional benefits of NO on platelet and leukocyte function. These collective findings inspired several randomized clinical trials and systematic reviews. These trials, however, do not support a role for inhaled NO in the routine management of patients with acute lung injury and ARDS. In fact, meta-analyses suggest this approach to patient care is more likely to cause harm through increased renal failure and possibly mortality. For intensive care clinicians, there are now sufficient data—in

quantity and quality—to suggest that inhaled NO should not be used in the routine management of patients with ARDS. Using the same physiologic rationale as for inhaled NO in ARDS, investigators have also tested the role for inhaled prostaglandins, reporting improved oxygenation in some studies. Direct comparisons of nebulized epoprostenol and inhaled NO have generally reported similar clinical effects between the two agents. Whether or not inhaled vasodilator therapy can make a difference in the setting of severe, life-threatening refractory hypoxemia is uncertain but any potential benefit should be weighed against the risk for extrapulmonary side effects such as renal failure, and its high cost. Keywords: acute respiratory distress syndrome, mechanical ventilation, nitric oxide, prostaglandins