Adverse respiratory effects of opioids for chronic breathlessness: learning lessons from chronic pain

Fear of fatal respiratory depression is a major driver limiting opioid prescription for persistent breathlessness in chronic obstructive pulmonary disease (COPD) [1–6], but is this fear warranted? In a recent systematic review and meta-analysis, VERBERKT et al. [7] did not detect significant or clinically relevant respiratory adverse events associated with opioid treatment for chronic breathlessness in COPD. Rather, they concluded that “clinicians’ fears of respiratory obtundation with low-dose opioids seem to be unfounded”. Here, we critically evaluate these conclusions

Tracheostomy in motor neuron disease

Tracheostomy-associated ventilation for the respiratory insufficiency caused by amyotrophic lateral sclerosis (motor neurone disease (MND)) is a complex issue with practical, ethical and economic dimensions. This article considers the current prevalence of tracheostomy in MND, the evidence for its benefit both for survival and quality of life, and the practicalities of its implementation. The decision to request invasive ventilatory support is among the most challenging for those living with MND. Neurologists should be prepared to discuss this option openly and objectively: we suggest a framework for discussion, including withdrawal of therapy

Tracheostomy in motor neuron disease

Tracheostomy-associated ventilation for the respiratory insufficiency caused by amyotrophic lateral sclerosis (motor neurone disease (MND)) is a complex issue with practical, ethical and economic dimensions. This article considers the current prevalence of tracheostomy in MND, the evidence for its benefit both for survival and quality of life, and the practicalities of its implementation. The decision to request invasive ventilatory support is among the most challenging for those living with MND. Neurologists should be prepared to discuss this option openly and objectively: we suggest a framework for discussion, including withdrawal of therapy

A challenging case of hypercapnic respiratory failure during pregnancy.

We describe a 40-year-old female who presented with progressive breathlessness and hypercapnic respiratory failure during pregnancy secondary to undiagnosed muscle-specific kinase myasthenia gravis. Her presentation was progressive and protracted, having over five contacts with healthcare professionals over nine months, many of these predating her pregnancy. Her atypical presentation for myasthenia with minimal limb weakness led to consideration of other causes of hypercapnic respiratory failure. Once diagnosed, she was treated with intravenous immunoglobulin and non-invasive ventilation. She gave birth to a pre-term infant by planned caesarean section. Her insidious presentation and the progressive nature of her breathlessness were unusual and our report highlights the predominant involvement of respiratory muscles in muscle-specific kinase myasthenia. Her pregnancy may have further delayed her diagnosis due the attribution of some symptoms to normal pregnancy. Early recognition and treatment of myasthenia gravis are important to prevent life-threatening complications

A challenging case of hypercapnic respiratory failure during pregnancy.

We describe a 40-year-old female who presented with progressive breathlessness and hypercapnic respiratory failure during pregnancy secondary to undiagnosed muscle-specific kinase myasthenia gravis. Her presentation was progressive and protracted, having over five contacts with healthcare professionals over nine months, many of these predating her pregnancy. Her atypical presentation for myasthenia with minimal limb weakness led to consideration of other causes of hypercapnic respiratory failure. Once diagnosed, she was treated with intravenous immunoglobulin and non-invasive ventilation. She gave birth to a pre-term infant by planned caesarean section. Her insidious presentation and the progressive nature of her breathlessness were unusual and our report highlights the predominant involvement of respiratory muscles in muscle-specific kinase myasthenia. Her pregnancy may have further delayed her diagnosis due the attribution of some symptoms to normal pregnancy. Early recognition and treatment of myasthenia gravis are important to prevent life-threatening complications

Pulmonary artery pressure increases during commercial air travel in healthy passengers.

BACKGROUND: It is not known whether the mild hypoxia experienced by passengers during commercial air travel triggers hypoxic pulmonary vasoconstriction and increases pulmonary artery pressure in flight. Insidious pulmonary hypertensive responses could endanger susceptible passengers who have cardiopulmonary disease or increased hypoxic pulmonary vascular sensitivity. Understanding these effects may improve pre-flight assessment of fitness-to-fly and reduce in-flight morbidity and mortality. METHODS: Eight healthy volunteers were studied during a scheduled commercial airline flight from London, UK, to Denver, CO. The aircraft was a Boeing 777 and the duration of the flight was 9 h. Systolic pulmonary artery pressure (sPAP) was assessed by portable Doppler echocardiography during the flight and over the following week in Denver, where the altitude (5280 ft/1610 m) simulates a commercial airliner environment. RESULTS: Cruising cabin altitude ranged between 5840 and 7170 ft (1780 to 2185 m), and mean arterial oxygen saturation was 95 +/- 0.6% during the flight. Mean sPAP increased significantly in flight by 6 +/- 1 mmHg to 33 +/- 1 mmHg, an increase of approximately 20%. After landing in Denver, sPAP was still 3 +/- 1 mmHg higher than baseline and remained elevated at 30 +/- 1 mmHg for a further 12 h. CONCLUSIONS: Pulmonary artery pressure increases during commercial air travel in healthy passengers, raising the possibility that hypoxic pulmonary hypertension could develop in susceptible individuals. A hypoxia altitude simulation test with simultaneous echocardiography ('HAST-echo') may be beneficial in assessing fitness to fly in vulnerable patients

Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.

Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers

Intravenous iron and chronic obstructive pulmonary disease: a randomised controlled trial

Background: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with COPD. Methods: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (age 69±8 years, haemoglobin 14.5±1.3 g/dL, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3±15.2%, mean±SD; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO2) at rest after one week. Secondary endpoints included daily SpO2, overnight SpO2, exercise SpO2, 6- minute walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures and exacerbation frequency. Results: Peripheral oxygen saturation was unchanged one week after FCM administration (difference between groups 0.8%, 95% CI −0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6-minute walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after one week (P=0.009). Modified MRC dyspnoea score was also significantly lower after FCM, and fewer participants reported scores ³2 in the FCM group, compared with placebo (33.3% vs. 66.7%, P=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs. 8.3%, P Conclusions: Ferric carboxymaltose did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well-tolerated, and produced improvements of exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies.</br

Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials.

CONTEXT: Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude. Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status, possibly acting through the transcription factor hypoxia-inducible factor, but the pathophysiological and clinical importance of this interaction is unknown. OBJECTIVE: To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind, placebo-controlled protocols conducted in October-November 2008. In the first protocol, 22 healthy sea-level resident men (aged 19-60 years) were studied over 1 week of hypoxia at Cerro de Pasco, Peru (altitude 4340 m). In the second protocol, 11 high-altitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru. INTERVENTION: In the first protocol, participants received intravenous infusions of Fe(III)-hydroxide sucrose (200 mg) or placebo on the third day of hypoxia. In the second protocol, patients underwent staged isovolemic venesection of 2 L of blood. Two weeks later, patients received intravenous infusions of Fe(III)-hydroxide sucrose (400 mg) or placebo, which were subsequently crossed over. MAIN OUTCOME MEASURE: Effect of varying iron availability on pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography. RESULTS: In the sea-level resident protocol, approximately 40% of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron, which reduced PASP by 6 mm Hg (95% confidence interval [CI], 4-8 mm Hg), from 37 mm Hg (95% CI, 34-40 mm Hg) to 31 mm Hg (95% CI, 29-33 mm Hg; P = .01). In the chronic mountain sickness protocol, progressive iron deficiency induced by venesection was associated with an approximately 25% increase in PASP of 9 mm Hg (95% CI, 4-14 mm Hg), from 37 mm Hg (95% CI, 30-44 mm Hg) to 46 mm Hg (95% CI, 40-52 mm Hg; P = .003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected. CONCLUSION: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00952302