Ipratropium bromide

What it is

Ipratropium bromide is a quaternary ammonium relative of atropine, given as a metered-dose inhaler, a nebuliser solution, or a nasal spray. The quaternary charge means little of it crosses out of the airway or nose into the rest of the body, which is why doses are in amounts measured in mcg per actuation and why systemic anticholinergic effects are uncommon rather than absent. It is also sold combined with albuterol.

What the research says

Inhaled, it blocks the vagal nerve signal that keeps airway muscle partly contracted, so the airway widens. In stable chronic obstructive pulmonary disease the Cochrane reviews find only small advantages over a short-acting beta2-agonist, and the Lung Health Study showed it does not slow the long-term loss of lung function. Added to a short-acting beta2-agonist in children having an asthma attack it cuts hospital admissions - that is the strongest evidence it has, and it is off-label in the US. As a nasal spray it reduces runny nose but not blocked nose. Its harms are the anticholinergic ones: dry mouth, nosebleeds from the spray, urinary retention in older men, angle-closure glaucoma if it reaches the eye, and rarely paradoxical bronchospasm.

Evidence grade: Well established.

How it works

Drug class: Short-acting inhaled antimuscarinic (anticholinergic) bronchodilator; a quaternary ammonium derivative of atropine

Nerve signals travelling down the vagus nerve release acetylcholine onto muscarinic receptors on airway muscle, which tightens it. Ipratropium blocks those receptors, so the signal does not get through and the muscle relaxes. It does not act on the inflammation underneath, and it does not work as fast as a beta2-agonist. (Source 1)

What it is used for

• It reliably widens the airways: in the registration trial, in people aged 40 and over with at least 10 pack-years of smoking, the average hourly improvement in FEV1 over six hours was 0.148 litres against 0.013 litres on placebo. But the Cochrane review of 11 trials in 3,912 people, searched to 2005, concluded the advantage over a short-acting beta2-agonist is small, and the label itself says it is not for treating an acute attack. Evidence: established. (Source 2)
• The nasal spray reduces runny nose and the label is explicit that it does not relieve congestion, sneezing or postnasal drip. The commonest harms are nosebleeds and nasal dryness, both clearly more frequent than on vehicle. Evidence: established. (Source 3)
• The strongest evidence ipratropium has, and it is not on the US label. Twenty trials in 2,697 children: adding an anticholinergic cut hospital admission from 23 to 17 per 100, risk ratio 0.73 (95% CI 0.63 to 0.85), number needed to treat 16, graded high-quality evidence. Nausea and tremor were less common than with the beta2-agonist alone. Evidence: established. (Source 4)
• Used alone instead of a beta2-agonist it performs worse: treatment failure odds ratio 2.27 (95% CI 1.08 to 4.75) versus a beta2-agonist. The reviewers conclude it is not appropriate as a single agent. Evidence: not-supported. (Source 5)
• Against placebo it produced small symptom and peak-flow gains - about a 7% peak-flow increase - but added to a short-acting beta2-agonist it gave no significant benefit on symptoms or peak flow. The review found no justification for routine add-on use. Evidence: not-supported. (Source 6)
• In 5,887 smokers followed for 5 years, ipratropium produced a small improvement in FEV1 that disappeared once the drug was stopped and did not change the rate of long-term decline. Smoking cessation did. Evidence: not-supported. (Source 7)
• Seven trials in 2,144 participants: all four trials that measured runny-nose severity favoured ipratropium, but it had no effect on nasal congestion and side effects were about twice as common (odds ratio 2.09, 95% CI 1.40 to 3.11). The 0.03% nasal product marketed in the US is labelled for perennial rhinitis, not the common cold. Evidence: limited. (Source 8)
• The Cochrane review found only three small trials, 103 patients in all, comparing ipratropium with an inhaled beta2-agonist in this setting: both produced an FEV1 improvement of 150-250 mL at 90 minutes with no difference between them, and no placebo comparison existed at all. The inhalation-solution label states the single-agent use in acute exacerbation has not been adequately studied and that the combination has not been shown better than either drug alone here. Evidence: unknown. (Source 9)

Interactions

• Other anticholinergic medicines (including oxybutynin, tolterodine, scopolamine, tricyclic antidepressants, and ipratropium by a second route) (label): Anticholinergic effects add up across drugs and across routes, so combining them increases dry mouth, urinary retention, blurred vision and eye-pressure problems. (Source 10)
• Short-acting beta2-agonists such as albuterol/salbutamol (nebulised together) (case reports): Therapeutically the two are often combined. But if nebulised mist reaches the eye the combination can precipitate acute angle-closure glaucoma, which neither does as readily alone. Limit: The numerals at the end of the quoted sentence are superscript reference markers flattened into the line by the publisher's file, not figures. This is a review of published case reports, so it shows the event happens, not how often. (Source 11)
• Other COPD and asthma drugs (sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids) (label): These are used together routinely, but with the exception of albuterol the label states no formal interaction studies were done. (Source 12)
• Alcohol (no documented ipratropium-specific interaction found) (label): We found no alcohol interaction in any of the ipratropium labels parsed or in the Cochrane reviews searched. What the labels do say is that interaction testing was limited: the inhaler's section names only the respiratory drugs it has been used with, and the nasal label states no controlled interaction trials were done at all. Limit: The PRECAUTIONS section this quote is taken from reports animal doses per square metre of body surface area, and the six occurrences of 'mg/m2' in the stored text are the label's 'mg/m²' with the superscript pulled down into the line. The trailing 2 is a squared unit, not part of the figure, and must never be read as one. (Source 13)
• Food (no documented ipratropium-specific interaction found) (label): No food interaction is documented. This is consistent with the pharmacology - ipratropium is inhaled or sprayed into the nose and very little reaches the bloodstream - but it rests on absence of evidence: the nasal label states no controlled clinical trials were conducted to investigate potential drug-drug interactions. Limit: The PRECAUTIONS section this quote is taken from reports animal doses per square metre of body surface area, and the six occurrences of 'mg/m2' in the stored text are the label's 'mg/m²' with the superscript pulled down into the line. The trailing 2 is a squared unit, not part of the figure, and must never be read as one. (Source 13)
• Dietary supplements (no documented ipratropium-specific interaction found) (label): No supplement interaction is documented in any of the ipratropium labels parsed or in the Cochrane reviews searched. The only interaction the labels assert is additive anticholinergic effect with other anticholinergic medicines - which would include an anticholinergic herbal preparation, though none is named - and the nasal label is explicit that no controlled interaction trials were done at all. Limit: The PRECAUTIONS section this quote is taken from reports animal doses per square metre of body surface area, and the six occurrences of 'mg/m2' in the stored text are the label's 'mg/m²' with the superscript pulled down into the line. The trailing 2 is a squared unit, not part of the figure, and must never be read as one. (Source 13)

Stopping it

• No withdrawal syndrome or dependence has been described for ipratropium, and none of the labels parsed carries a tapering instruction. What stopping does is remove the benefit: in the Lung Health Study the small FEV1 gain vanished once the bronchodilator was discontinued at the end of the study, which is also why it was judged not to be disease-modifying. (Source 7)
• The one circumstance in which the labels say to stop at once rather than taper is a bad reaction: paradoxical bronchospasm, which the label calls life threatening. (Source 14)
• The same applies to a hypersensitivity reaction - the label says therapy should be stopped at once and alternative treatment considered. (Source 15)
• For the nasal spray the question of rebound was looked at directly, and the answer was negative: the trials found no clinically significant increase in rhinorrhoea, postnasal drip, sneezing or congestion on stopping - unlike decongestant sprays, which do rebound. (Source 16)

What goes wrong

Starting an inhaled anticholinergic was associated with a higher risk of acute urinary retention in older men with COPD, especially those with benign prostatic hyperplasia. (Source 17)

• Case-control study, Moderate certainty.
• Size: 565,073 individuals with COPD screened; 9,432 men and 1,806 women developed acute urinary retention.
• Who: People aged 66 or older with COPD in linked population databases in Ontario, Canada, April 2003 to March 2009; each case matched to up to 5 controls.
• How long: 6 years of database follow-up.
• Result: Men newly started on an inhaled anticholinergic: adjusted odds ratio 1.42 (95% CI 1.20-1.68) versus non-users. With evidence of benign prostatic hyperplasia, 1.81 (1.46-2.24). Using both a short- and a long-acting inhaled anticholinergic: 1.84 (1.25-2.71) versus monotherapy and 2.69 (1.93-3.76) versus non-users.
• Funding: not stated in the abstract (population database study)

Limit of this finding: A nested case-control study of dispensing records: it shows association, not cause, and cannot separate the drug from the severity of the lung disease that prompted it. It also pools short- and long-acting inhaled anticholinergics, so the figures are not ipratropium-specific. The odds ratios are given without absolute risks.

Men who just initiated a regimen of IACs were at increased risk for AUR compared with nonusers (adjusted odds ratio [OR], 1.42; 95% confidence interval [CI], 1.20-1.68). In men with evidence of benign prostatic hyperplasia, the risk was increased further (OR, 1.81; 95% CI, 1.46-2.24). Men using both short- and long-acting IACs had a significantly higher risk of AUR compared with monotherapy users (OR, 1.84; 95% CI, 1.25-2.71) or nonusers (2.69; 1.93-3.76).

Nebulised ipratropium combined with salbutamol has repeatedly been reported to precipitate acute angle-closure glaucoma when the mist reaches the eye. (Source 11)

• Expert review, not systematic, Very low certainty.
• Size: not stated - a review of published case reports.
• Who: Patients receiving nebulised bronchodilators.
• How long: not applicable.
• Result: The review describes numerous reports of acute angle-closure glaucoma in patients exposed to both nebulised ipratropium and salbutamol, attributing it to a synergistic mechanism - ipratropium dilating the pupil while salbutamol increases aqueous humour production - and notes the exposure can be avoided with goggles during nebuliser treatments.
• Funding: not stated.

Limit of this finding: This is a narrative review of case reports with no denominator, so it establishes that the event happens, not how often. A reader should not infer a risk rate from it. In the quoted sentences the trailing numerals - 'salbutamol.11,18' - are superscript reference markers that the publisher's file has pulled down into the line. They are citation numbers, not measurements, and the same flattening elsewhere in the paper turns 'an increase in IOP' followed by references 10 and 12 into what looks like a decimal. The references themselves are not identified in the quoted passage.

However, there are numerous reports of AACG occurring in patients exposed to a combination of both nebulized ipratropium and salbutamol.11,18 These two medications act synergistically to precipitate AACG—ipratropium causes pupillary dilation and salbutamol causes increase in aqueous humor production. Inadvertent exposure to the eye can be avoided with the use of goggles during nebulizer treatments.

The inhaler's own trials show a modest excess of anticholinergic effects over placebo, and the label records glaucoma, urinary retention and paradoxical bronchospasm from wider use. (Source 18)

• Randomized trial, Moderate certainty.
• Size: 1,010 COPD patients across two 12-week studies and one 1-year open-label study (243 on HFA versus 128 on placebo in the controlled comparison)
• Who: People with COPD in the registration programme.
• How long: 12 weeks and 1 year.
• Result: Twelve weeks, ipratropium HFA versus placebo: dry mouth 4% versus 2%, nausea 4% versus 2%, dizziness 3% versus 2%, dyspnoea 8% versus 4%, bronchitis 10% versus 6%, urinary tract infection 2% versus 1%, headache 6% versus 8%. Overall 9.3% of patients on the HFA inhaler reported at least one adverse event the investigator judged drug-related, most often dry mouth (1.6%) and bitter taste (0.9%). Reported with wider use: precipitation or worsening of narrow-angle glaucoma, halo vision, corneal oedema, mydriasis, acute eye pain, urinary retention, tachycardia, constipation and paradoxical bronchospasm; and allergic-type reactions including skin rash, pruritus, angioedema of the tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions.
• Funding: industry (manufacturer's label data)

Limit of this finding: COPD exacerbation was reported in 8% on ipratropium HFA versus 13% on placebo and 14% on the older CFC inhaler, and headache was more common on placebo - so several rows of this table do not run in the direction a reader might assume. The one-year column has no placebo arm. The final paragraph of this section, now included, is the one that carries the life-threatening reactions: angioedema of the tongue, lips and face, laryngospasm and anaphylaxis.

As an anticholinergic drug, cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, halo vision, conjunctival hyperemia, corneal edema, mydriasis, acute eye pain, dry throat, hypotension, palpitations, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been reported with the use of ATROVENT. Additional adverse reactions identified for ATROVENT seen in clinical trials include throat irritation, stomatitis, mouth edema, and vision blurred.

The nasal spray causes nosebleeds and nasal dryness clearly more often than vehicle. (Source 16)

• Randomized trial, Moderate certainty.
• Size: 356 patients on ipratropium nasal spray versus 347 on vehicle.
• Who: People with perennial rhinitis in four multicentre vehicle-controlled trials.
• How long: four or eight weeks.
• Result: Epistaxis 9.0% versus 4.6% (the label's footnote splits this into frank epistaxis in 7.0% versus 2.3% and blood-tinged mucus in 2.0% versus 2.3%), nasal dryness 5.1% versus 0.9%, other nasal symptoms 3.1% versus 1.7%, nasal irritation 2.0% versus 1.7%, pharyngitis 8.1% versus 4.6%, nausea 2.2% versus 0.9%, headache 9.8% versus 9.2%, upper respiratory tract infection 9.8% versus 7.2%. The section's post-marketing part, with no rates attached, additionally reports skin rash, angioedema including of the throat, tongue, lips and face, generalised urticaria, laryngospasm and anaphylactic reactions, as well as urinary retention and precipitation or worsening of narrow-angle glaucoma.
• Funding: industry (manufacturer's label data)

Limit of this finding: The 9.0% epistaxis row is a combined category: the label's footnote splits it into 7.0% frank epistaxis plus 2.0% blood-tinged mucus, and the vehicle's 4.6% into 2.3% plus 2.3%. Read that way, the whole excess is frank nosebleeds (7.0% versus 2.3%) while blood-tinged mucus was no more common on the drug than on vehicle (2.0% versus 2.3%). A reader should not take 9.0% as the rate of frank nosebleeds. The rhinitis row has no figures at all in either arm - it is a heading for the nasal dryness, irritation and other-symptom rows beneath it. The serious reactions - anaphylaxis, angioedema of the throat, tongue, lips and face, laryngospasm - come from post-marketing reports with no denominator, so no rate can be attached to them.

Table 1: % of Patients Reporting Events+ + This table includes adverse events which occurred at an incidence rate of at least 2.0% in the ipratropium bromide group and more frequently in the ipratropium bromide group than in the vehicle group. Ipratropium Bromide Nasal Spray 0.03% (n=356) Vehicle Control (n=347) Incidence % Discontinued % Incidence % Discontinued % Headache 9.8 0.6 9.2 0.0 Upper respiratory tract infection 9.8 1.4 7.2 1.4 Epistaxis¹ 9.0 0.3 4.6 0.3 Rhinitis² Nasal dryness 5.1 0.0 0.9 0.3 Nasal irritation³ 2.0 0.0 1.7 0.6 Other nasal symptoms⁴ 3.1 1.1 1.7 0.3 Pharyngitis 8.1 0.3 4.6 0.0 Nausea 2.2 0.3 0.9 0.0 ¹ Epistaxis reported by 7.0% of ipratropium bromide patients and 2.3% of vehicle patients, blood-tinged mucus by 2.0% of ipratropium bromide patients and 2.3% of vehicle patients. ² All events are listed by their WHO term; rhinitis has been presented by descriptive terms for clarification. ³ Nasal irritation includes reports of nasal itching, nasal burning, nasal irritation, and ulcerative rhinitis. ⁴ Other nasal symptoms include reports of nasal congestion, increased rhinorrhea, increased rhinitis, posterior nasal drip, sneezing, nasal polyps, and nasal edema.

Ipratropium can cause the opposite of what it is given for - a paradoxical tightening of the airways that the label calls life threatening. (Source 14)

• Official position, Certainty not rated.
• Size: not stated - a labelled warning, not a rate.
• Who: People using the inhaler for COPD.
• How long: not applicable.
• Result: No frequency is given. The label states the effect can be life threatening and that treatment should be stopped if it occurs. Bronchospasm also appears in the label's list of hypersensitivity reactions and in the inhalation-solution label's list of immediate hypersensitivity reactions, and lower respiratory events including bronchospasm were the commonest reason for stopping the nebuliser solution in its 12-week trials.
• Funding: industry (manufacturer's label)

ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening. If this occurs, treatment with ATROVENT HFA should be stopped and other treatments considered.

What the evidence supports

Adding inhaled ipratropium to a short-acting beta2-agonist in children having an asthma attack reduced hospital admissions, on high-quality evidence. (Source 4)

• Systematic review, High certainty.
• Size: 2,697 randomised children aged 1 to 18 across 20 trials (15 studies, 2,497 children, for the admission outcome)
• Who: Children presenting with predominantly moderate or severe asthma exacerbations; 9 of 20 trials at low risk of bias.
• How long: the emergency presentation and immediate aftermath.
• Result: Hospital admission risk ratio 0.73 (95% CI 0.63 to 0.85), graded high-quality evidence: 23 of 100 children admitted on beta2-agonist alone versus 17 (95% CI 15 to 20) with the anticholinergic added - a number needed to treat of 16 (95% CI 12 to 29). Lung function, clinical score at 120 minutes, oxygen saturation at 60 minutes and need for repeat bronchodilators also favoured the combination; relapse rates did not differ. Fewer children reported nausea and tremor.
• Funding: not stated (Cochrane review)

Limit of this finding: The review's own age figures do not agree: the results describe 2,697 children aged one to 18, while its eligibility rule was 18 months to 18 years, and three of the trials included some infants under 18 months. The authors also qualify the result in their conclusion: the apparent trend towards more benefit with more intensive treatment and more severe asthma did not reach statistical significance.

The addition of an anticholinergic to a SABA significantly reduced the risk of hospital admission (risk ratio (RR) 0.73; 95% confidence interval (CI) 0.63 to 0.85; 15 studies, 2497 children, high-quality evidence). In the group receiving only SABAs, 23 out of 100 children with acute asthma were admitted to hospital compared with 17 (95% CI 15 to 20) out of 100 children treated with SABAs plus anticholinergics. This represents an overall number needed to treat for an additional beneficial outcome (NNTB) of 16 (95% CI 12 to 29).

Ipratropium widens the airways in COPD measurably more than placebo, sustained over 12 weeks. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 505 of 507 randomised COPD patients evaluated.
• Who: Adults 40 and over with COPD, over 10 pack-years, FEV1 below 65% and FEV1/FVC below 70%.
• How long: 12 weeks.
• Result: Day 1: average hourly improvement in adjusted mean FEV1 over the six hours post-dose 0.148 litres on ipratropium versus 0.013 litres on placebo; mean peak improvement 0.295 litres versus 0.138 litres. Day 85: 0.141 versus 0.014 litres hourly, peak 0.295 versus 0.140 litres. Median time to a 15% FEV1 rise about 15 minutes, peak at 1 to 2 hours, lasting 2 to 4 hours.
• Funding: industry (manufacturer's registration trials, in the label)

Limit of this finding: These are the manufacturer's registration trials in people aged 40 and over who had smoked at least 10 pack-years and already had moderate to severe airflow obstruction, so the figures do not describe milder disease or younger people. The label points to a figure (Figure 1) that is not reproduced with the text.

During the six hours immediately post-dose on day 1, the average hourly improvement in adjusted mean FEV1 was 0.148 liters for ATROVENT HFA (42 mcg) and 0.013 liters for placebo. The mean peak improvement in FEV1, relative to baseline, was 0.295 liters, compared to 0.138 liters for placebo. During the six hours immediately post-dose on day 85, the average hourly improvement in adjusted mean FEV1 was 0.141 liters for ATROVENT HFA (42 mcg) and 0.014 liters for placebo. The mean peak improvement in FEV1, relative to baseline, was 0.295 liters, compared to 0.140 liters for placebo.

What the evidence does not support

Over five years in smokers with early COPD, ipratropium did not slow the decline in lung function, and the small gain it did produce vanished when the drug was stopped. (Source 7)

• Randomized trial, High certainty.
• Size: 5,887 smokers aged 35 to 60 randomised across 10 clinical centres.
• Who: Male and female smokers with spirometric signs of early chronic obstructive pulmonary disease.
• How long: 5 years.
• Result: The bronchodilator produced a relatively small improvement in FEV1 that was non-cumulative and reversed after discontinuation; it did not influence the long-term decline of FEV1. The smoking-intervention groups, by contrast, showed significantly smaller declines, with the largest benefit in those who achieved sustained cessation.
• Funding: not stated in the abstract (NHLBI-sponsored multicentre trial)

Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1.

Compared with a long-acting beta2-agonist in stable COPD, ipratropium was worse on lung function and no different on quality of life, exacerbations or symptoms. (Source 19)

• Systematic review, Low certainty.
• Size: 2,652 participants across 7 trials.
• Who: Non-asthmatic adults with stable COPD.
• How long: at least 4 weeks per trial.
• Result: Significantly greater change in favour of salmeterol in morning peak flow and FEV1; no significant differences in quality of life, exacerbations or symptoms. Formoterol also conferred some morning peak-flow benefit over ipratropium. Adding ipratropium to salmeterol improved post-bronchodilator lung function, rescue beta-agonist use and quality of life, though not consistently.
• Funding: not stated (Cochrane review)

Limit of this finding: Two cautions. The authors' conclusion talks about exercise tolerance, but no exercise-tolerance outcome appears anywhere in the results it rests on - those report morning peak flow, FEV1, quality of life, exacerbations and symptoms. And the combination benefit is hedged by the authors themselves as 'modest' and 'not consistent'. This is also the 2006 version of the review, searched to August 2005.

Monotherapy comparison (six studies): There was a significantly greater change in favour of salmeterol in morning PEF and FEV1. There were no significant differences in quality of life, exacerbations, or symptoms.

Ipratropium alone is worse than a beta2-agonist for acute asthma in children and should not be used as a single agent. (Source 5)

• Systematic review, Very low certainty.
• Size: 171 children across 4 trials for the failure comparison; 6 studies included overall.
• Who: Children over two years old with acute asthma.
• How long: the acute episode.
• Result: Treatment failure odds ratio 2.27 (95% CI 1.08 to 4.75) for anticholinergic alone versus beta2-agonist, and 2.65 (95% CI 1.2 to 5.88) versus the combination (4 trials, 173 children). The review notes the studies were of unclear quality and limited by small sample sizes. Anticholinergic use was not associated with significant side effects.
• Funding: not stated (Cochrane review)

Limit of this finding: Four small trials totalling 171 and 173 children, of 'overall unclear quality', and the outcomes could not be pooled beyond treatment failure and hospitalisation. A reader should not read the odds ratios as precise, and should note the review found no significant side effects in the same breath as finding it less effective. The review's searching ran only to April 2011 and it covers anticholinergics given as the only bronchodilator in children over two, not the combination used in practice.

In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta(2)-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta(2)-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations.

Adding an anticholinergic to a short-acting beta2-agonist for chronic asthma in adults gave no significant benefit on symptoms or peak flow. (Source 6)

• Systematic review, Low certainty.
• Size: 205 participants across 13 studies versus placebo; 440 patients across 9 studies for the add-on comparison.
• Who: Adults with chronic asthma; studies longer than 24 hours.
• How long: longer-term studies (over 24 hours)
• Result: Against placebo: daytime dyspnoea weighted mean difference -0.09 (95% CI -0.14, -0.04; 3 studies, 59 patients) and morning peak flow WMD 14.38 litres/min (95% CI 7.69, 21.08; 3 studies, 59 patients), which the review says 'equates to approximately a 7% increase over placebo'. Against a short-acting beta2-agonist alone, the combination gave no evidence of any significant difference in symptom scores or peak flow rates.
• Funding: not stated (Cochrane review)

Limit of this finding: The placebo-comparison estimates rest on 3 studies and 59 patients, and the review says methodological quality was poorly reported with reservations about study quality. A reader should not read the 7% peak-flow figure as a clinically meaningful benefit - the review itself calls the clinical significance small. The review's own text is inconsistent about its size, giving '13 studies involving 205 participants' and '9 studies involving 440 patients' in the same sentence, and two of its published confidence intervals have an unmatched bracket. Its searching ran only to August 2003.

Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies.

In acute COPD exacerbation the evidence comparing ipratropium with a beta2-agonist rests on three small trials and no placebo comparison exists at all. (Source 9)

• Systematic review, Very low certainty.
• Size: 103 patients across 3 studies.
• Who: People with acute exacerbations of COPD.
• How long: one study of 7 days' regular therapy; two single-dose crossover studies measured at 90 minutes.
• Result: Both treatments improved FEV1 by 150-250 mL at 90 minutes, with a mean difference between them of 10 mL (95% CI -220, 230 mL). In one 10-patient crossover study arterial PaO2 rose 5.8 mm Hg (SEM 3.0) at 30 minutes with ipratropium against a fall of 6.2 (1.2) mm Hg with metaproterenol, but the difference was gone by 90 minutes. No respiratory-symptom data were reported.
• Funding: not stated (Cochrane review)

Limit of this finding: The confidence interval on the FEV1 difference (-220 to 230 mL) is as wide as the effect either drug produced, so 'no difference' here means the trials were far too small to find one. The beta2-agonists used were fenoterol and metaproterenol, not the salbutamol and terbutaline used today, and the crossover studies had no washout period. A reader should not take this as evidence the two are equivalent. This is the 2001 version of the review, with searching current to 2000, resting on 3 trials and 103 patients, and the review itself notes none of the included studies used salbutamol or terbutaline - the short-acting inhalers in common use now. One sentence in the published abstract begins 'The was no difference', the review's own typographical error for 'There was'.

We identified no placebo-controlled comparisons of beta-2 agonists. Three studies permitted comparison of ipratropium to an inhaled beta-2 agonist. These studies included a total of 103 patients. The beta2-agonists used were: fenoterol and metaproterenol. One study was a parallel group trial of regular therapy for seven days. The other two were cross over studies of single dose treatments, with efficacy measured 90 min post dose. There was no washout period between treatments. Both treatments produced an improvement in forced expiratory volume (FEV1) after 90 min in the range 150-250 ml. The was no difference between treatments, mean difference in FEV1 10 ml; 95% CI -220, 230 ml.

Where the evidence is mixed

Regular long-term ipratropium offers only small advantages over a short-acting beta2-agonist in stable COPD. (Source 20)

• Systematic review, Low certainty.
• Size: 3,912 participants across 11 randomised controlled trials.
• Who: Non-asthmatic adults with stable COPD, treated at least 4 weeks.
• How long: at least 4 weeks per trial.
• Result: Small benefits of ipratropium over a short-acting beta2-agonist on lung function and on health-related quality of life, plus a reduction in the requirement for oral steroids. Combination therapy beat a beta2-agonist alone on post-bronchodilator lung function and oral steroid requirement but not on quality of life. The reviewers conclude the advantages are small if the aim is to improve lung function, symptoms and exercise tolerance.
• Funding: not stated (Cochrane review)

Limit of this finding: The review reports these benefits as directions without numbers in its abstract, so the size of 'small' is not quantified there. A reader should not infer a specific effect size from this summary. This is the 2006 version of the review, with searching current to 2005, so it predates the long-acting inhalers that now dominate COPD treatment.

Eleven studies (3912 participants) met the inclusion criteria of the review. Small benefits of ipratropium over a short-acting beta-2 agonist were demonstrated on lung function outcomes. There were small benefits in favour of ipratropium on quality of life (HRQL), as well as a reduction in the requirement for oral steroids. Combination therapy with ipratropium plus a short-acting beta-2 agonist conferred benefits over a short-acting beta-2 agonist alone in terms of post-bronchodilator lung function. There was no significant benefit of combination therapy in subjective improvements in HRQL, but again there was a reduction in the requirement for oral steroids.

Intranasal ipratropium reduces runny nose in the common cold but not blocked nose, and roughly doubles the odds of a side effect. (Source 8)

• Systematic review, Low certainty.
• Size: 2,144 participants across 7 trials (1,959 in the 4 trials of rhinorrhoea severity)
• Who: Children and adults with the common cold.
• How long: the cold episode.
• Result: All four studies of rhinorrhoea severity reported statistically significant changes favouring ipratropium. Nasal congestion showed no significant change between groups. Side effects were more frequent with ipratropium, odds ratio 2.09 (95% CI 1.40 to 3.11) - commonly nasal dryness, blood-tinged mucus and epistaxis. Overall risk of bias in the included studies was moderate.
• Funding: not stated (Cochrane review)

Limit of this finding: The only pooled number in this part of the review is the harm estimate. The runny-nose result is reported as all four trials being consistent and statistically significant, with no pooled effect size, so how much it helps is not quantified here. The 0.06% nasal strength associated with the common cold did not appear in our DailyMed search of US products, so this use is off-label on the products we could find.

Nasal congestion was reported in four studies and was found to have no significant change between the two groups. Two studies found a positive response in the IB group for the global assessment of overall improvement. Side effects were more frequent in the IB group, odds ratio (OR) 2.09 (95% confidence interval (CI) 1.40 to 3.11). Commonly encountered side effects included nasal dryness, blood tinged mucus and epistaxis.

Where the research disagrees

Whether ipratropium or a beta2-agonist is the better regular bronchodilator in stable COPD

• Appleton and colleagues, Cochrane Review versus short-acting beta2-agonists, systematic review, 11 trials, 3,912 participants: The available data from the trials included in this review suggest that the advantage of regular long term use of ipratropium alone or in combination with a short-acting beta-2 agonist or over a beta-2 agonist alone are small, if the aim is to improve lung function, symptoms and exercise tolerance. (Source 21)
• Appleton and colleagues, Cochrane Review versus long-acting beta2-agonists, systematic review, 7 trials, 2,652 participants: The available data from the trials suggest that there is little difference between regular long term use of IpB alone and salmeterol if the aim is to improve COPD symptoms and exercise tolerance. However, salmeterol was more effective in improving lung function variables. (Source 19)

Whether ipratropium belongs in asthma treatment

• Griffiths and Ducharme, Cochrane Review of acute asthma in children, systematic review, 20 trials, 2,697 children, high-quality evidence for hospital admission: Children with an asthma exacerbation experience a lower risk of admission to hospital if they are treated with the combination of inhaled SABAs plus anticholinergic versus SABA alone. They also experience a greater improvement in lung function and less risk of nausea and tremor. (Source 4)
• Westby and colleagues, Cochrane Review of chronic asthma in adults, systematic review, 13 placebo-controlled and 9 add-on studies: Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit (Source 6)

How much

• Reference intake: Dosing is set by the prescriber and differs by route - inhaler, nebuliser solution and nasal spray are not interchangeable. As a position, the FDA label (DailyMed SPL for ATROVENT HFA, effective 2025-11-05) designates the product for maintenance treatment of bronchospasm associated with COPD and states plainly that the product is not for the initial treatment of an acute episode. (Source 22)
• Upper limit: As a position, each label sets its own ceiling per route; the nebuliser solution's adverse-reactions section notes that headache, mouth dryness and worsening COPD symptoms become more common once the total daily amount reaches or exceeds 2,000 mcg. (Source 23)
• Studied: The COPD registration trial compared 42 mcg and 84 mcg of the HFA inhaler with 42 mcg of the older CFC inhaler and their placebos, where 42 mcg is two inhalations of 21 mcg. (Source 2)
• Studied: The Cochrane review of acute childhood asthma reports that most trials used a fixed protocol of three doses of 250 mcg or two doses of 500 mcg of nebulised ipratropium alongside a short-acting beta2-agonist over 30 to 90 minutes. (Source 4)
• Studied: The Lung Health Study prescribed ipratropium from a metered-dose inhaler three times daily, two puffs per time, for five years. (Source 7)
• Studied: The nasal perennial-rhinitis trials used 42 mcg per nostril two or three times daily for four or eight weeks. (Source 16)

A common belief, and what the research shows

The belief: Ipratropium is a reliever inhaler, so it can be used like albuterol when breathing suddenly gets worse.

What the research shows: The label is explicit that it is not. On the label's own measurement the median time to a 15% or greater rise in FEV1 was within about 15 minutes, with the peak at 1 to 2 hours, which is why the inhaler's label says it is for maintenance and “is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.” In an asthma attack in children it has a real role, but added to a fast-acting beta2-agonist, not instead of one: used alone it performed worse than a beta2-agonist (treatment failure odds ratio 2.27, 95% CI 1.08 to 4.75).

Questions and answers

What is it?

Ipratropium bromide is an anticholinergic - more precisely an antimuscarinic - bronchodilator, a quaternary ammonium relative of atropine. It is breathed in from a metered-dose inhaler or a nebuliser, or sprayed into the nose. The permanent positive charge on the molecule keeps most of it in the airway or nose instead of the bloodstream, which is why the amounts are measured in amounts measured in mcg per puff and why body-wide anticholinergic effects are the exception rather than the rule. (Source 1)

What does it do in the body?

The vagus nerve releases acetylcholine onto muscarinic receptors on airway muscle, which keeps the muscle partly contracted. Ipratropium blocks those receptors, so the signal does not arrive and the muscle relaxes, widening the airway. In the nose the same blockade cuts the watery secretion that makes a nose run - and only that: the label states plainly it does not relieve congestion, sneezing or postnasal drip. It does nothing to the inflammation underneath either condition. (Source 1)

Is it good or bad for you?

Good in the right place, useless or harmful in the wrong one. Added to a short-acting beta2-agonist in a child having an asthma attack it cut hospital admission from 23 to 17 per 100 children, risk ratio 0.73 (95% CI 0.63 to 0.85) on high-quality evidence, with fewer reports of nausea and tremor. Used alone instead of a beta2-agonist in the same children it performed worse. In stable COPD its advantage over a beta2-agonist is small; it does not slow the long-term loss of lung function; and in older men it is associated with urinary retention. (Source 4)

How do you get more of it?

Ipratropium is a prescription drug delivered to a surface, not something to increase in the body. No food or supplement contains it. What changes how much reaches the body is the device and the technique: the inhaler and the nebuliser solution and the nasal spray are different products at different strengths and are not interchangeable, and the label limits it to maintenance use rather than rescue. The one thing that reliably raises exposure is using more than prescribed, which the nebuliser label links to more headache, dry mouth and worsening symptoms. (Source 23)

If it is harmful, what reduces it?

There is no way to clear ipratropium faster and no antidote in ordinary use. Because so little gets into the bloodstream, the practical answer to a bad effect is to stop giving it, and the labels say exactly that in two situations: paradoxical bronchospasm, which the label calls life threatening and says should prompt stopping and considering other treatments; and a hypersensitivity reaction, where therapy should be stopped at once. For the eye problem the measure is prevention rather than removal - keeping the spray and the nebulised mist out of the eyes. (Source 14)

Why might someone be low in it or missing it?

Nobody is naturally short of ipratropium - it is a drug, not a body constituent, so there is no deficiency. The equivalent question is why someone might not be getting the effect, and the common answers are the device not being used properly, the drug being used as a reliever when it is a maintenance treatment, or it simply not being the right drug: against a long-acting beta2-agonist in stable COPD it was worse on lung function and no better on quality of life, exacerbations or symptoms. (Source 19)

Which whole foods contain it or feed it?

None. Ipratropium is a synthetic drug given to the lining of the airway or nose; no whole food contains it and no food feeds it. No food interaction is documented either, which is consistent with how little of it is absorbed - but that absence rests on the labels not having tested it: the nasal label states no controlled clinical trials were conducted to investigate potential drug-drug interactions, and the inhaler's label says that apart from albuterol no formal interaction studies were done. (Source 13)

What happens if you do not have it?

Going without it means going without the bronchodilation. In the COPD registration trial that gap is measurable: over the six hours after a dose the average hourly improvement in FEV1 was 0.148 litres on ipratropium against 0.013 litres on placebo, with a peak improvement of 0.295 against 0.138 litres, and the same difference was still there on day 85. What going without does not do is change the disease: the Lung Health Study found the drug's small benefit vanished on stopping and it never altered the long-term decline in lung function. (Source 2)

How can you test for it?

There is no blood test for ipratropium in ordinary care and none is needed - the test of whether it works is spirometry, specifically FEV1 before and after a dose, which is how its effect was established. The label's own benchmark is a 15% rise in FEV1, reached at a median of about 15 minutes, peaking at 1 to 2 hours and lasting 2 to 4 hours in most patients. For the harms there is no assay either: eye pressure, prostate symptoms and urinary retention are looked for clinically. (Source 2)

References

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2. DailyMed (FDA Structured Product Label), Boehringer Ingelheim Pharmaceuticals, Inc.. ATROVENT HFA (ipratropium bromide) inhalation aerosol, section 14 CLINICAL STUDIES. 2025. Read the source
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11. Journal of Current Glaucoma Practice. Drug-induced Acute Angle-closure Glaucoma: A Review.. 2019. PMID 32435123, DOI 10.5005/jp-journals-10078-1261. Read the source
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13. DailyMed (FDA Structured Product Label), Lupin Pharmaceuticals, Inc.. IPRATROPIUM BROMIDE nasal solution 0.03%, PRECAUTIONS. 2026. Read the source
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18. DailyMed (FDA Structured Product Label), Boehringer Ingelheim Pharmaceuticals, Inc.. ATROVENT HFA (ipratropium bromide) inhalation aerosol, section 6.1 Clinical Trials Experience. 2025. Read the source
19. Cochrane Database of Systematic Reviews. Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease.. 2006. PMID 16856113, DOI 10.1002/14651858.CD006101. Read the source
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21. Cochrane Database of Systematic Reviews. Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease.. 2006. PMID 16625543, DOI 10.1002/14651858.CD001387.pub2. Read the source
22. DailyMed (FDA Structured Product Label), Boehringer Ingelheim Pharmaceuticals, Inc.. ATROVENT HFA (ipratropium bromide) inhalation aerosol, section 5.1 Use for Maintenance Treatment Only. 2025. Read the source
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