Page 671 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

490 PART 4: Pulmonary Disorders

subcutaneously), and their accompanying toxicity, can nearly always be patients on theophylline, including those with nontoxic levels. Two of
avoided. The longer acting β -agonist formoterol (but not salmeterol) six patients with this rhythm disturbance died suddenly during hospital-
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has a fast onset of action and has been demonstrated to provide equally ization, without antecedent ventricular ectopy.
effective bronchodilation in mild COPD exacerbations when admin- Consistent with guidelines from expert panels we rarely if ever use
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istered in high doses but may be associated with mild worsening of intravenous aminophylline and then only as an adjunct to other, more
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hypoxemia. There is no published experience with the once daily effective management (NIV, standard bronchodilators and steroids).
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β -agonist, indacaterol in ACRF. Generally, because of concerns about Aminophylline is initiated as a loading dose of 5 mg/kg infused over
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activity as a partial receptor antagonist, significant additional cost, and 30 minutes, then continued as an intravenous infusion at a rate of
therapeutic equivalence, we do not recommend long acting inhaled β - 0.5 mg/kg/h. In patients who are already taking an oral methylxanthine,
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agonists during the acute phase of ACRF. β -agonists are established to intravenous loading and maintenance dosing should be guided by serum
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cause minor negative perturbations in V/Q imbalance and gas exchange levels. Given the mild efficacy of the drug and its substantial toxicity, it
https://kat.cr/user/tahir99/
in stable COPD. However, this effect is not seen in AECOPD. 135 is difficult to justify empirical partial loading doses.
Anticholinergic Therapies Selective PDE Inhibitors Selective inhibitors of Type IV PDE (such as roflu-
Ipratropium The anticholinergic agent ipratropium bromide is as effective milast) that have pleiotropic effects on lung inflammation and remod-
as metaproterenol in the treatment of ACRF, 126,135 and may even be better eling appear to have a beneficial effects in reducing the occurrence of
in stable COPD. An additional advantage of this drug is that, compared to AECOPD with chronic administration—particularly in patients with
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, rather than moderate and severe disease. However, as for many newer therapies,
metaproterenol, its use is associated with a small rise in Pa O 2 PDE-IV inhibitors have not been evaluated in the treatment of COPD
the small decline usually seen with β -agonists. The addition of ipratro-
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pium to a regimen containing inhaled β -agonists yields incremental exacerbations or for patients with ACRF and have a side-effect profile
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benefit in patients with stable COPD but as discussed above, does not that limits enthusiasm for this drug class in ACRF.
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result in improved bronchodilation in acute exacerbations. The usual Corticosteroids Patients with ACRF given methylprednisolone, 0.5 mg/kg
dose of ipratropium in ACRF is three puffs every 30 to 60 minutes. Much every 6 hours, in addition to standard bronchodilators show greater
higher doses (400 μg) have been shown to be optimal in stable patients improvement in spirometric values than patients who do not receive this
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with COPD, but this question has not been examined in ACRF. 136 drug. This benefit is demonstrable at least as early as 12 hours, and in
Tiotropium Tiotropium, a recently released long-acting inhaled anticho- some studies of patients with asthma, possibly after 1 hour. In another
linergic, has demonstrated promise in patients with stable COPD by study of patients with ACRF, 0.8 mg/kg of prednisolone given intrave-
nously reduced the inspiratory resistance and PEEPi when measured at
reducing symptoms, decline in FEV , and frequency of exacerbations. 145
1
The Understanding Potential Long-Term Impacts on Function with 90 minutes.
In a meta-analysis of 10 studies involving 1051 patients with
Tiotropium (UPLIFT) conducted in 5993 stable COPD patients dem-
onstrated that daily tiotropium reduced significantly COPD-related AECOPD, there were significantly fewer treatment failures within
30 days in patients given corticosteroid treatment, odds ratio (OR) 0.50;
morbidity, improved health-related quality of life (HRQOL) irrespective
of disease severity and slowed significantly lung function decline in 95% CI 0.36 to 0.69 and hazard ratio 0.78; 95% CI 0.63 to 0.97; NNT
to avoid one treatment failure was 10 patients (95% CI 7-16). Length
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patients not using inhaled corticosteroids or other long-acting broncho-
137
dilators with an acceptable safety profile. To date, however, there is no of hospital stay was also shorter (mean difference −1.22 days; 95% CI
−2.26 to −0.18) and FEV improvement at 72 hours was 140 mL greater
published experience with tiotropium as a specific therapy for ACRF. 1
(95% CI 90-190 mL). This was consistently associated with significant
Phosphodiesterase Inhibitors improvements in breathlessness and blood gases. Despite this there
Aminophylline Aminophylline is a mildly effective nonselective phos- was no significant effect on mortality but an increased likelihood of an
phodiesterase (PDE) inhibitor in patients with COPD. In addition to its adverse event associated with corticosteroid treatment, OR 2.33; 95% CI
actions as a bronchodilator, aminophylline has salutary effects on the 1.60 to 3.40. Hyperglycemia was of particular concern (OR 4.95; 95%
diaphragm in experimental settings. These include inotropy and resis- CI 2.47-9.91). 146
tance to fatigue in patients, although the clinical relevance of these find- Although there is significant debate about the optimal dose and
ings is yet to be demonstrated, and recent studies have challenged the duration of steroids, current guidelines recommend methylpred-
12
underpinnings of these clinical trials. Whether aminophylline should nisolone, 0.5 to 1 mg/kg every 6 hours. In a large retrospective study of
138
be given to patients with ACRF is controversial, and recent trends show almost 80,000 patients admitted to predominantly community medical
it falling out of favor. A controlled trial in patients hospitalized for an centers for AECOPD, 92% were initially treated with high-dose intra-
AECOPD failed to show any benefit of aminophylline when added to venous steroids (median total dose 600 mg, prednisone equivalents,
a standard regimen of β -agonists and corticosteroids. On the other IQR 35-751 mg), and 8% received lower dose oral treatment (median
139
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hand, theophylline causes demonstrable (although generally mild) 60 mg prednisone equivalent dose, IQR 40-120 mg). In multivariable
147
physiologic improvement in stable COPD patients, even when superim- analysis, the risk of treatment failure was no different for patients treated
posed on a regimen of β -agonist or on a combination of high-dose intravenously or orally, (OR 0.93; 95% CI 0.84-1.02). In a propensity-
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inhaled β -agonist plus ipratropium. Meta-analysis of 4 randomized matched analysis, the risk of treatment failure was significantly lower
140
2
controlled trials including 169 patients demonstrated no improvement among orally treated patients (OR, 0.84; 95% CI 0.75-0.95), as was
in bronchodilation or hospital LOS in patients with acute exacerbations. length of stay and cost. Despite these encouraging data in patients
147
However, not all patients had severe ACRF. Toxicity of these drugs is not admitted to an ICU, our preference remains to initiate parenteral
141
substantial, including arrhythmogenesis and CNS effects. In the meta- corticosteroid therapy in patients with ACRF as the primary presenta-
analysis, there were fivefold greater odds of gastrointestinal symptoms in tion requiring ICU admission, and particularly if mechanical ventilatory
theophylline treated patients. Daily serum level measurement is neces- support is required.
141
sary for safe use, especially in light of the significant interactions with Since these drugs have important detrimental effects on metabolic,
other drugs. Even when serum levels are considered to be therapeutic, muscular, and immune function, their continued use should be reevalu-
aminophylline may have important toxicity. In a multivariate analysis of ated after the first 72 hours with a transition to oral therapy when
100 patients receiving theophylline, drug level was the most important tolerated. Although no effect of corticosteroids on respiratory muscle
predictor of arrhythmia, ahead of age and gender. Both atrial and ven- function can be shown in the short term (<2 weeks ), they do con-
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142
tricular arrhythmias were seen and correlated with theophylline level. tribute to muscle weakness in the long term. No additional benefit is
67
In the group with therapeutic levels, 48% had arrhythmias. Particularly derived from prolonging steroid therapy beyond 2 weeks. A possible
worrisome was the finding of multifocal atrial tachycardia (MAT) in alternative may be to use high doses of the nebulized steroid budesonide
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