Clinical Pearl 80: Does Albuterol help in Bronchiolitis?

An 11 month old male is having difficulty breathing. The baby appears comfortable but with intercoastal retractions, and nasal congestion. His RR is 42 bmp,  SpO2 is 93% on RA, HR is 120bpm. He has wheezing throughout both lung fields and mother tells you that this is his 4^th day with this symptoms. Would Albuterol be your next step in treatment?

The scenario clearly shows a child that meets criteria for bronchiolitis; for years we’ve been trying to figure out what can we do to make this patient better, and for years bronchodilators have been one of the first line treatments, but does it really work?

Scribani MB et al. (Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014.) suggests that bronchodilators may provide modest short-term clinical improvement but do not affect overall outcome, may have adverse effects, and increase the cost of care. This is a meta-analysis of randomized trials and systematic reviews that included 30 trials representing 1992 infants with bronchiolitis. It demonstrated that oxygen saturation did not improve with bronchodilators. Outpatient bronchodilator treatment did not reduce the rate of hospitalization, and inpatient bronchodilator treatment did not reduced length of stay in the hospital. The clinical score and oximetry outcome showed significant heterogeneity with questionable clinical importance. Multiple adverse effects where recorded such as tachycardia, oxygen desaturation and tremors. The review concluded that given the adverse side effects and the expense associated with these treatments, bronchodilators are not effective in the routine management of bronchiolitis.

Per American Academy of Pediatrics most recent guidelines (Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis. Pediatrics. 2014) Clinicians should not administer albuterol or epinephrine to infants and children with a diagnosis of bronchiolitis (Evidence Quality: B; Recommendation Strength: Strong Recommendation)

But, should I at least try it?

A one-time trial of inhaled bronchodilators (albuterol or epinephrine) may be warranted for infants and children with bronchiolitis and severe disease, as this group generally was excluded from trials evaluating inhaled bronchodilators in children with bronchiolitis.

In addition, a subset of young children with the clinical syndrome of bronchiolitis may have virus-induced wheezing or asthma and may benefit from inhaled bronchodilator therapy. In a prospective multicenter study by Jonathan M. Mansbach et al. (Children hospitalized with rhinovirus bronchiolitis have asthma-like characteristics. J Pediatr. 2016 May) of children hospitalized with bronchiolitis, children with rhinovirus-associated bronchiolitis were more likely than those with respiratory syncytial virus-associated bronchiolitis to respond to bronchodilators as they present similar to asthmatic patients, and are usually excluded from other studies as it is more common on patients >12 months of age. 

In conclusion, after reviewing the available literature, the use of albuterol in patients with bronchiolitis might be attempted once and evaluate for response, but if no desirable response, the continued use of bronchodilators will only increase side effects and cost with no added benefit, and will give wrong reassurance to parents that there is an effective treatment for Bronchiolitis besides letting the disease run its course. 

Clinical Pearl 79: Nebulized Lidocaine

By: Katherine Tokarczyk, MD

      Michael Carr, M.D.

Lidocaine is well known to the medical community as a first line local anesthetic and cardiac antiarrhythmic agent. It acts by blocking voltage gated sodium channels in neurons (pain receptors) and in cardiac cells. In recent years its other implications have emerged into common practice for various clinicians. It has been used in the past for bronchoscopy to suppress coughing in the peri-procedural period. Perhaps more relevant to the acute care clinician, nebulized lidocaine can also be used to suppress retractable cough in patients with reactive airway disease such as asthma or COPD. Can this be used in every day practice for patients with asthma and intractable cough?

Lidocaine has recently been shown to be beneficial in asthma therapy. It can prevent eosinophilic inflammation, over production of mucus, and peri-bronchial fibrosis. Studies have recognized lidocaine as a steroid-sparing agent it has been shown to decreased airway hyperactivity.

Lidocaine inhibits conduction of nerve impulses by decreasing membrane permeability to sodium resulting increased the threshold for excitation and diminishing progression of membrane depolarization. As a cough suppressant, it thought to inhibit conduction of afferent nerve impulses and will therefore suppress the cough reflex induced by mechanical and chemical stimuli. It also prevents eosinophil activation by cytokines and thus damage to epithelial and smooth muscle cells.

What about Lidocaine toxicity? This is a concern when serum levels of lidocaine are over 5mcg/L.  Symptoms include lighthheadness, tremors, hallucinations, seizures, arrhythmias, paresthesia, and respiratory arrest.  One should use caution when giving this medication to patients with hepatic disease due to decreased rates of drug metabolism and elimination rates.  A safe range of nebulized lidocaine is100-200mg per dose. Doses as high as, 600mg have been used in young healthy patients, however.  Serum levels of greater than 1 mcg/mL are not reached until 300 to 400 mg is administered to the airway, either by means of direct instillation (i.e. down an ET tube) or by nebulization.

Dosing:

Adults: Dose up to 3mg/kg/dose (for 70kg adult, 3mg/kg is 210 mg)

If using 2% (20mg/mL) Lidocaine, 10 mL is equal to 200 mg. Dilute in 5mL normal saline Prior to nebulization.

If using 4% (40mg/mL) Lidocaine, 5mL is equal to 200mg. Dilute in 10 mL normal saline prior to nebulization.

Adults can receive 4% Lidocaine 3ml in normal saline 3-4x/day

Children: Dose up to 2.4 mg/kg/dose. Only Lidocaine 2% (20 mg/mL) should be used in children.

Children can receive 0.8mg/kg/dose to 2.5 mg/kg/dose in NS 3-4 x/day

The Evidence

Hunt et al, in a randomized, placed-controlled study in patients with mild to moderate asthma (50 people), 25 received lidocaine and 25, placebo. Inclusion criteria for the study required each subject to have prebronchodilator FEV1 64%-125%, and treatment with daily-inhaled glucocorticoids and bronchodilator for at least two months. Each subject used peak flow values and took their medication for two weeks. Everyone inhaled either nebulized saline or lidocaine 4% 100mg, four times per day. They reduced their inhaled glucocorticoids dosage by half each week for three weeks and stopped by week four. They continued nebulized treatment for total eight weeks with their bronchodilators. They recorded peak flow in the morning and at bedtime, using a scoring sheet to report their symptoms. Ultimately, those treated with 2.5 mL of 4% Lidocaine (100mg) 4 times daily decreased their inhaled glucocorticoid dosage by half each week. Also when placebo was compared to lidocaine for eight weeks, asthma severity decreased in the lidocaine group as measured by FEV1, night-time awakening, overall symptoms, bronchodilator use and blood eosinophil blood concentration (all P values  <0.05).

A literature search using PubMed, international pharmaceutical abstracts and Cochrane Library evaluating the use of nebulized lidocaine in intractable cough and asthma yielded seven studies evaluating nebulized lidocaine for intractable cough. Efficacy was reported with doses 10-400 mg. One case series of nebulized lidocaine 1 to 4% every 4-6 hours with albuterol produced relief of cough in 21 patients with obstructive, restrictive or infective airway disease. In a single blinded clinical trial, 127 patients with cough secondary to COPD compared nebulized lidocaine 1mg/kg and terbutaline 5mg for cough suppression.  Data was compiled by filling out a questionnaire. The results showed improvements in cough severity compared to baseline assessments, but they were not significant (P=0.4).

A review of five different clinical trials showed varying results of improvement in PTFs and steroid-sparing effects. One study (N= 99) nebulized lidocaine 40 mg twice daily with steroid-naïve patients with mild-moderate asthma.  They measured the change from baseline FEV1 after 12 weeks of treatment. The results overall didn’t show improvement in PFTs in FEV1%.  The other four studies, however, showed significant improvement in baseline PFTs. The studies included in this review had limitations, however, such as small sample size, design flaws, and inconsistencies in adjunctive therapies.

Although nebulized lidocaine is not first-line therapy for in intractable cough and asthma, it does provide an alternative treatment option in patients who cannot tolerate or are unresponsive to other treatments.  Keep in mind, however that appropriate monitoring precautions should be used to ensure patient safety.

References:

1) Hunt LW, Frigas E, Butterfield JH, et al. J Treatment of asthma with nebulized lidocaine: a randomized, placebo-controlled study. Allergy Clin Immunol. 2004;113:853-859.

2) Decco ML¹, Neeno TA, Hunt LW, et al, Nebulized lidocaine in the treatment of severe asthma in children: a pilot study. Annals of Alleregy, Asthma Immunology 82; 1999.

3) Magda F. Serra, Ph.D., Edna A. et al. Nebulized Lidocaine prevents Airway inflammation, peribronchial fibrosis and mucus production in a Murine model of asthma. Anesthesiology 2012; 117: 580-591.

4) Rachel M Slaton, Rachel H Thomas, Joseph Wallace Mbathi  Evidence for Therapeutic Uses of Nebulized Lidocaine in the Treatment of Intractable Cough and Asthma. The Annals of Pharmacotherapy 2013;47

5) Hunt LW, Swedlund HA, Gleich GJ. Effect of nebulized lidocaine on severe glucocorticoid-dependent asthma., Mayo Clin Proc 1996;71: 361-368.

Clinical Pearl 78: Does Naloxone Really Cause Pulmonary Edema?

Case: 23 y/o male who is unresponsive found by his friends in an ally. Policearrive on scene first and find the patient to have a respiratory rate of four andpinpoint pupils. The decision is made to give 0.4 mg of intranasal Naloxone. The respiratory rate has improved to six per minute however his pupilsremain pinpoint and oxygen saturation is only 88% on room air. You administer an additional 0.4 mg IV and place the patient on a non-rebreather mask and shortly after the patient is alert and oriented to person, place, time, and situation. The patient becomes tachypneic to a rate of 30, is saturating at 90% on non-rebreather, is coughing up pink frothy sputum, has crackles diffusely on exam and is now in severe respiratory distress. The patient denies a history of hypertension, cardiac disease, or respiratory disease. Wha thappened?

The safety of naloxone has been questioned over many years however with its more controversial accessibility to non-medically trained personnel such as law enforcement officers and family members of potential victims one of the more life threatening questionable side effects has raised some concern. Does the administration of naloxone cause pulmonary edema?

A widely accepted mechanism of how naloxone causes pulmonary edema is adrenergic overload. The sudden reversal causes catecholamine release that increases stroke volume, blood pressure, pulse strength, cardiac index, and plasma concentrations of epinephrine. These catecholamines also result in increased pulmonary-capillary hydrostatic pressure causing increased permeability.

A confusing aspect of this is that opioids alone can cause pulmonary edema. Sir William Osler in 1880 noted in an autopsy of a patient who died of narcotic overdose had pulmonary edema which was much earlier than the development of naloxone. One proposed mechanism is that histamine release secondary to opioid use causes secretion of proteinaceous material from lung capillaries resulting in accumulation of fluid. A second is that with respiratory suppression there is a rapid increase in negative pulmonary pressure from the upper airway obstruction leading to the movement of fluid out of the pulmonary capillaries and into the interstitial and alveolar space.

So did the patient in our case have pulmonary edema as a result of using the opioid or naloxone was administered?

According to Boyer et al. naloxone has been mistakenly implicated as a cause of pulmonary edema. Boyer notes that studies have shown that pulmonary edema is not secondary to large doses of naloxone nor by means of continuous infusion as in a naloxone drip and that auscultatory signs of pulmonary edema, which are difficult to auscultate in an apneic patient, become apparent only after naloxone restores ventilation.

The development of non-cardiogenic pulmonary edema, more correctly identified as acute lung injury (ALI) is multifactorial and cannot be predicted. The overall incidence is low with rates ranging from 0.2% - 3.6% and studies suggest that patients who develop pulmonary edema following opiate overdose and naloxone administration usually do so within 4 hours however it has been seen in one case up to 8 hours.

So does Narcan cause pulmonary edema? There is no convincing evidence suggesting that it does. There is data and evidence supporting theories of the patient developing pulmonary edema because of using opioids as well as for naloxone potentiating a physiologic cascade of events that causes the edema. There have been may case reports of naloxone being suspected as causing non-cardiogenic pulmonary edema in both hospital and prehospital settings but to this date, there has been no trial published. Subsequently, naloxone induced pulmonary edema remains unproven.

1. Kienbaum P et al. Profound increase in epinephrine concentration in plasma and cardiovascular stimulation after mu-opioid receptor blockade in opioid-addicted patients during barbiturate-induced anesthesia for acute detoxification. Anesthesiology 1998;88(5):1154-61.

PubMed

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Overdose Reversal. Retrieved August 01, 2017, from

https://www.ebmconsult.com/articles/mechanism-naloxone-relatedpulmonary-

edema-opiate-opioid-overdose-reversal

3. Sporer, K. A., & Dorn, E. (2001). Heroin-Related Noncardiogenic Pulmonary Edema. Chest, 120(5), 1628-1632.

doi:10.1378/chest.120.5.1628

4. Bhaskar B, Fraser JF. Negative pressure pulmonary edemarevisited: Pathophysiology and review of management. Saudi J Anaesth.

2011;5(3):308-13

5. Boyer EW. Management of opioid analgesic overdose. N Engl J

Med. 2012;367(2): 146-55

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https://www.ebmconsult.com/articles/incidence-naloxone-pulmonaryedema-

after-reversal-opioid-heroin-overdose