In a recent Diabetes, Obesity & Metabolism analysis of individuals aged =70 years with type 2 diabetes, almost 40% with recommended HbA1c levels (which indicate blood glucose levels) were over-treated.
An analysis of published studies and reports indicates that a number of herbal products may affect the properties of prescription drugs, leading to alterations in the drugs’ effectiveness as well as potentially dangerous side effects.
The benefits of low-intensity physical activity, such as standing, walking or doing household chores, can be more health beneficial than once thought. According to a study from Karolinska Institutet published in the journal Clinical Epidemiology, replacing half an hour’s sedentariness a day with everyday activity reduces the risk of fatal cardiovascular disease by 24 per cent.
A study led by researchers at Keele University has found the risk of death in later life due to coronary heart disease doubles in women who give birth prematurely.
There is no evidence to support the practice of parents providing alcohol to their teenagers to protect them from alcohol-related risks during early adolescence, according to a prospective cohort study in Australia published in The Lancet Public Health journal.
When investigators compared initial bone parameters with changes in those parameters over time in postmenopausal women, they found that initial measurements were significantly associated with women’s risk of fracture.
The Synapse meets pharmacist Anna Formosa who also happens to be an applied drama practitioner, and widely known for her creative community projects especially her latest intergenerational project ‘Darba Waħda…’
The safety of travelling in patients suffering from chronic lung conditions is a frequently encountered problem amongst healthcare professionals. The objective of this paper is to review currently available literature, with the aim of clarifying such issues for doctors dealing with such concerns. The article will describe the effect of altitude on healthy and diseased lungs, assessment tools to be utilised when assessing patients with suspected or diagnosed chronic lung conditions and international guideline recommendations for chronic lung conditions.
COPD - Chronic obstructive pulmonary disease
FEV1 - Forced expiratory volume in one second
CPAP - Continuous positive airway pressure
CXR - Chest X-ray
SpO2 - Peripheral capillary oxygen saturation
PaO2 - Arterial partial pressure of oxygen
BTS - British Thoracic Society
In recent years there has been a progressive rise in the number of people who travel by air.1 The ease of travel as well as the increasing availability of lower cost travel makes journeys accessible to older or less financially advantaged travellers.2 In addition, advances in the monitoring of many chronic respiratory diseases as well as the availability of medications have improved quality in the lifestyle of such patients, allowing chronically ill patients to consider the possibility of air travel. It has become common for people with lung disease to request to travel and in turn seek advice from their medical practitioners about related issues. Surprisingly, reports of serious incidents concerning travellers with lung disease are relatively rare. Since respiratory problems are estimated to make up about 11% of in-flight emergencies it is reasonable to assume that the burden of risk surrounding the flight itself, and later disruption of the journey, is significant.3
Fight Environment and Altitude Effects
Commercial aircraft are pressurised to cabin altitudes of up to 8000 feet (2438m) although this ceiling may be exceeded in emergencies. Pressurization of the aircraft cabin is achieved using exterior air that is compressed and mixed with filtered and re-circulated cabin air. Up to 50% of the cabin air is not re-circulated and is expelled, to be replaced with exterior air, with 20–30 complete air exchanges occurring per hour.4 At that altitude, the partial pressure of oxygen falls to the equivalent of breathing 15.1% oxygen at sea-level.
The rapid reduction in pressure associated with ascent is usually well tolerated by the healthy lung. At cabin altitude even normal people can occasionally desaturate but will generally compensate by increasing alveolar ventilation,3 such that people with healthy lungs remain asymptomatic throughout the flight.
On the other hand, apart from the usual health risks of airline flight, the principal additional challenge for patients with chronic respiratory disease is exposure to hypobaric hypoxia. Patients suffering from chronic respiratory illness may have mild hypoxaemia, which may even go unrecognized at times. Altitude exposure may worsen hypoxaemia in pulmonary disease. Compensatory pulmonary mechanisms may be inadequate in patients with lung disease despite normal sea-level oxygen requirements. In addition, compensatory cardiovascular mechanisms may be less effective in some patients who are unable to increase cardiac output.4 Such patients may be vulnerable to the relatively minor pressure changes, causing an enlargement of a pre-existing pneumothorax or rupture of an emphysematous bulla or other spaces containing air.3 The physiological compensation for acute hypoxaemia is mild to moderate hyperventilation, limited by the fall in arterial carbon dioxide tension (PaCO2) together with a moderate tachycardia.2
If there is doubt about the patient’s ﬁtness to ﬂy and if there are co-morbidities affecting ﬁtness, assessment is advised. In general, the patient’s respiratory condition should be stable and the patient must have recovered from any recent exacerbation before travel. It is recommended that those patients with the following conditions should be assessed with at least, a history and physical examination:
- Previous air travel intolerance with signiﬁcant respiratory symptoms (dyspnoea, chest pain, confusion or syncope)
- Severe chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) <30% predicted) or asthma
- Bullous lung disease
- Severe (vital capacity <1 litre) restrictive disease (including chest wall and respiratory muscle disease), especially with hypoxaemia and/or hypercapnia
- Cystic ﬁbrosis
- Co-morbidity with conditions worsened by hypoxaemia (cerebrovascular disease, cardiac disease or pulmonary hypertension)
- Pulmonary tuberculosis
- Within six weeks of hospital discharge for acute respiratory illness
- Recent pneumothorax
- Risk of or previous venous thrombo-embolism
- Pre-existing requirement for oxygen, continuous positive airway pressure (CPAP) or ventilator support.2
During such an assessment patients should have their condition optimised, where possible, thus decreasing the risk of complications and potentially reducing the severity of hypoxaemia.
History, Physical Examination, and Spirometry
As part of a pre-flight screening evaluation, a detailed history and physical examination should be performed. Any previous flying history should therefore be explored, as this may yield important information on the symptoms or complications that may have occurred during or after previous air travel. Physicians should also consider the ﬂight duration, destination, as well as the control of the disease.
In the absence of any contraindication, the American Thoracic Society recommends that spirometry should be performed on patients with a history of acute or chronic lung disease or with symptoms suggestive of lung disease. Pulse oximetry at rest should also be done, with arterial blood gas confirmation in addition to this, if hypercapnia is suspected.4
Assessing the Risk for Hypoxaemia
Undoubtedly, people with respiratory disease who use long term oxygen treatment will need to continue using oxygen during a flight.3 The doubt arises in patients who have borderline hypoxaemia at sea level, in which case these patients need to be assessed thoroughly.
A number of methods of assessment for hypoxaemia risk during air travel are available. These include:
- Sea-level measurement of SpO2and PaO2
- The use of equations to predict hypoxaemia at altitude
- Hypoxic challenge testing, performed under either normobaric or hypobaric conditions.
Measuring SpO2 at sea level to risk-stratify patients has become recognized as a less reliable predictor of in-flight SpO2 compared to other methods. In the 2002 British Thoracic Society (BTS) guidelines, an SpO2 of 92–95% without risk factors or SpO2 greater than 95% was used to indicate that no further testing was warranted.5 However, in one study, 23% of patients having an SpO2 greater than 96%, tested by hypoxic challenge testing, experienced significant hypoxaemia warranting in-flight oxygen supplementation.6 In another study of 100 COPD patients, stratified on the basis of SpO2 thresholds from the 2002 BTS algorithm, who underwent pulse oximetry and normobaric hypoxic challenge testing, the sensitivity and specificity for these SpO2 thresholds were only 59% and 72%, respectively.7 Despite this method being readily available, cheap, and not laborious, this tool is not considered sufficiently robust to screen patients.
Predictive equations have also been used to estimate the risk of hypoxaemia at high altitude; they incorporate sea-level measurements of PaO2 and other parameters such as FEV1 or anticipated cabin altitude.8,9 Many of the equations consistently overestimated the need for supplemental oxygen, thus incurring unnecessary additional cost.4 The novel non-linear predictive models represent a low cost option for the prediction of significant hypoxia during flight and perform better than SpO2 in identifying those patients who require more formal assessment with hypoxic challenge testing.10
Hypoxic challenge testing, though costly and time-consuming, is now the preferred method to assess risk of hypoxaemia at altitude.4 It uses a decreased (normobaric) fraction of inspired oxygen (FiO2) to simulate the hypoxic conditions at altitude.4 It is performed in a specialist lung function unit after referral to a respiratory specialist.2 However, it is not available locally, rendering it difficult to advise our local patients accordingly, even in a hospital setting. The hypoxic challenge test is not a ‘ﬁtness to ﬂy’ test but is used to determine whether a patient needs in-ﬂight oxygen; most importantly, even with in-ﬂight oxygen and/or ventilator support, safety cannot be guaranteed.2 In fact, in one particular study, in PaO2 hypoxic altitude simulation testing, no difference was identified between COPD patients with and without respiratory symptoms.11
FEV1 is also a useful marker of clinical severity. However, neither resting sea-level oxygen saturations nor FEV1 appear to predict hypoxaemia or complications accurately during or after air travel in patients with respiratory disease.2
Based on the current literature, it can be concluded that air travel is safe for most patients. However, those at risk of hypoxia can benefit from supplemental in-flight oxygen.12
Further research is required to determine whether a symptom-based approach, for instance the Medical Research Council dyspnoea scale or clinical exercise testing might be more reliable for screening.2
Contraindications to Commercial Air Travel
Certain patients suffering from pulmonary disease should be advised to avoid flying, either because of high risk of deterioration of their pre-existing condition or else, because they pose a risk to others. These include:
- Ongoing pneumothorax with persistent air leak
- Major haemoptysis
- Infectious tuberculosis
- Usual oxygen requirement at sea level at a ﬂow-rate exceeding 4L/min.2,4
Chronic Lung Diseases
Obstructive Pulmonary Disease (Asthma and COPD)
Before travel, patients should have their condition optimised, with the least possible symptoms as well as minimal use of reliever medication. They should carry their inhalers, including spacer, at all times. A patient should also be treated and has recovered from an exacerbation before being advised to travel. A bronchodilator given via a spacer is as effective as a nebuliser. For acute exacerbations on board, the patient’s own bronchodilator inhaler, ideally with a spacer, should be taken, and the dose repeated until symptomatic relief is obtained. According to BTS recommendations, it is advised that patients with severe or brittle asthma or severe COPD (FEV1<30% predicted) should consult their respiratory specialist beforehand for optimisation of their condition and the patient may consider carrying an emergency supply of prednisolone in addition to their usual medication.2 A recent study has suggested that hypoxic challenge testing should be performed for patients suffering from severe asthma.13
Positive sputum cultures should ideally be treated so as to optimize the patients’ condition. Bronchodilators should be prescribed as necessary. Nebulised antibiotics or nebulised bronchodilators are not generally required.2
Severe or symptomatic anaemia should be corrected beforehand, as should hyponatraemia, hypokalaemia and hypercalcaemia. Treatment (radiotherapy, chemotherapy and/or stenting) for major airway obstruction, including upper airways stridor, should be complete before travel and sufficient time passed to enable the physician/oncologist to conﬁrm stability. Patients with lymphangitis carcinomatosa or superior vena cava obstruction should only ﬂy if essential, and must have in-ﬂight oxygen available. Pleural effusions should be drained as much as possible before travel. Patients with major haemoptysis should not ﬂy.2
Pre-ﬂight assessment is advised for those with acute and chronic respiratory infections. Patients with infectious tuberculosis must not travel by public air transportation. World Health Organization guidelines state that ‘physicians should inform all infectious and potentially infectious tuberculosis patients that they must not travel by air on any commercial ﬂight of any duration until they are sputum smear-negative on at least two occasions’.2
Interstitial Lung Disease
Patients should be carefully assessed. Supplemental oxygen should be considered if travelling at high altitude destinations. Carrying an emergency supply of antibiotics and prednisolone is recommended and medical advice on their usage should be given in the case of an exacerbation.2,4
Neuromuscular Disease and Chest Wall Disease
International guidelines recommend that all patients with conditions causing severe extra-pulmonary restriction, including those needing home ventilation, should undergo hypoxic challenge testing before travel, if available. The decision to recommend in-ﬂight oxygen and/or non-invasive ventilation must be made on an individual clinical basis. 2,4
Cystic Lung Disease
In addition to hyperinflation within communicating airways, at an altitude of 8,000 feet, Boyle’s law predicts there will be a 38% increase in the size of closed air-filled pockets within the body.14 This gas expansion may be associated with an increased risk of pneumothorax in patients with bullous or cystic lung disease. In patients with chronic lung disease who are already at risk of hypoxaemia, the development of a pneumothorax in-flight could be a significant challenge. A previous history of pneumothorax may be more relevant in patients with lung disease, as rapid changes in barometric pressure may precipitate recurrence.4
Obstructive Sleep Apnoea Syndrome
A doctor’s letter is required outlining the diagnosis and necessary equipment, and patients should keep their CPAP machine in the cabin. Alcohol and sedatives should be avoided before and during travel.2
Patients with a closed pneumothorax should not travel on commercial ﬂights (with the exception of the very rare case of a loculated or chronic localised air collection which has been very carefully evaluated). Patients who have had a pneumothorax must have a chest X-ray (CXR) to conﬁrm resolution before a ﬂight, and flying is not advised for at least seven days after confirmation of resolution. For patients who have suffered a traumatic pneumothorax, the delay after full radiographic resolution should ideally be two weeks. Prognosis is good for those who opt for surgical intervention as a treatment measure. The risk of recurrence is higher in those with coexisting lung disease and does not fall signiﬁcantly for at least one year. 2,4 Alternative forms of transport might be considered for other patients.
In patients who underwent thoracic surgery with drain insertion, chest radiography is required after drain removal to ensure full expansion of the lung. Patients who have a pneumothorax after drain removal should not travel on commercial ﬂights until full re-expansion has been conﬁrmed on CXR. If chest radiography after drain removal conﬁrms full re-expansion, it is prudent to wait for seven days before air travel. Any symptoms or signs suggesting the possibility of a pneumothorax should prompt a further CXR before air travel.2,4
Advance planning is of utmost importance. Our patients must be advised to seek medical attention before flying. Patients should be advised to carry around a list of their prescription medication, including oxygen, and to take an adequate supply to last the whole trip. For patients who make use of portable oxygen concentrators, they must check in advance to see if the airline allows this and notify them accordingly. If needed, one should book extra services with the airline in advance, such as in-ﬂight oxygen or wheelchairs, and check with the airline regarding the carriage of nebuliser machines, ventilators or CPAP machines. Travellers must also ensure that proper arrangements are made for travel insurance. The physician might also consider prescribing an emergency supply of antibiotics, with or without prednisolone, to be used as required by the patient, in case of an exacerbation whilst abroad.
When evaluating patients for air travel, it is important to highlight the following points:
Even at 35,000 feet, different types of commercial aircraft can have widely differing cabin altitudes, ranging from an equivalent of approximately 5,400 feet to 8,000 feet.15 In addition, commercial aircraft may also vary their cruising altitude a number of times during the flight, which in turn can alter cabin pressure.15,16
Respiratory symptoms may occur despite having a pre-flight assessment. One study found 18% of patients with COPD developed respiratory symptoms despite having a pre-flight evaluation.17
Flight duration is another important factor to consider. Longer flight durations are associated with increased symptoms,6 particularly when lasting over three hours.18
The levels of activity of the patient during the flight should also be considered. Patients with COPD, restrictive lung disease, and cystic fibrosis demonstrate significant worsening of hypoxaemia at simulated altitude with a workload equivalent to that of walking around the aircraft cabin.19-21
Being diagnosed with a chronic lung condition does not mean that the patient can no longer travel but there are a number of limitations and implications. Patients must be advised to carefully plan their travel and to seek medical advice accordingly.
International guidelines recommend that hypoxic challenge testing should be considered for patients with chronic lung diseases, since such patients are at risk of developing significant hypoxaemia and complications during air travel. In the absence of its availability locally, medical professionals must ensure that such patients have their respiratory status optimised, following a thorough assessment with the help of available tools, and that expert advice is sought when deemed necessary.
Conflicts of interest
The author declares that there are no conflicts of interest.
- Rio FG, Clau LB, Macario CC, Celli BR, Sanglas JA, Mangado NG et al. Air Travel and Respiratory Disease. Recommendations of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). Archivos de Bronconeumologia (English edition) 2007; 43(2):101-125.
- BTS Air Travel Working Group. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2011; 66(Supp. 1).
- Morgan MD. Air Travel and Respiratory Disease. BMJ 2002; 325(7374):1186-1187.
- Nicholson TT, Sznajder JI. Fitness to Fly in Patients with Lung Disease. Annals ATS 2014; 11(10):1614-1622.
- British Thoracic Society Standards of Care Committee. Managing passengers with respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2002; 57:289–304.
- Coker RK, Shiner RJ, Partridge MR. Is air travel safe for those with lung disease? Eur Respir J 2007; 30:1057–1063.
- Akerø A, Christensen CC, Edvardsen A, Ryg M, Skjønsberg OH. Pulse oximetry in the preflight evaluation of patients with chronic obstructive pulmonary disease. Aviat Space Environ Med 2008; 79:518–524.
- Dillard TA, Berg BW, Rajagopal KR, Dooley JW, Mehm WJ. Hypoxemia during air travel in patients with chronic obstructive pulmonary disease. Ann Intern Med 1989; 111:362–367.
- Gong H Jr, Tashkin DP, Lee EY, Simmons MS. Hypoxia-altitude simulation test: evaluation of patients with chronic airway obstruction. Am Rev Respir Dis 1984; 130:980–986.
- Billings CG, Wei HL, Thomas P, Linnane SJ, Hope-Gill BD. The prediction of in-flight hypoxaemia using non-linear equations. Respir Med2013; 107(6):841-7.
- Edvardsen A, Ryg M, Akerø A, Christensen CC, Skjønsberg OH. COPD and air travel: does hypoxia-altitude simulation testing predict in-flight respiratory symptoms? Eur Respir J2013; 42(5):1216-23.
- Spoorenberg ME, van den Oord MH, Meeuwsen T, Takken T. Fitness to Fly Testing in Patients with Congenital Heart and Lung Disease. Aerosp Med Hum Perform2016; 87(1):54-60.
- George PM, Orton C, Ward S, Menzies-Gow A, Hull JH. Hypoxic Challenge Testing for Fitness to Fly with Severe Asthma. Aerosp Med Hum Perform2016; 87(6):571-4.
- García RF, Borderías CL, Casanova MC, Celli BR, Escarrabill SJ, González MN et al. Air travel and respiratory diseases [in Spanish]. Arch Bronconeumol 2007; 43:101–125.
- Cottrell JJ. Altitude exposures during aircraft flight: flying higher. Chest 1988; 93:81–84.
- Hampson NB, Kregenow DA, Mahoney AM, Kirtland SH, Horan KL, Holm JR et al. Altitude exposures during commercial flight: a reappraisal. Aviat Space Environ Med 2013; 84:27–31.
- Dillard TA, Beninati WA, Berg BW. Air travel in patients with chronic obstructive pulmonary disease. Arch Intern Med 1991; 151:1793–1795.
- Muhm JM, Rock PB, McMullin DL, Jones SP, Lu IL, Eilers KD et al. Effect of aircraft-cabin altitude on passenger discomfort. N Engl J Med 2007; 357:18–27.
- Christensen CC, Ryg M, Refvem OK, Skjønsberg OH. Development of severe hypoxaemia in chronic obstructive pulmonary disease patients at 2,438 m (8,000 ft) altitude. Eur Respir J 2000; 15:635–639.
- Christensen CC, Ryg MS, Refvem OK, Skjønsberg OH. Effect of hypobaric hypoxia on blood gases in patients with restrictive lung disease. Eur Respir J 2002; 20:300–305.
21.Fischer R, Lang SM, Brückner K, Hoyer HX, Meyer S, Griese M et al. Lung function in adults with cystic fibrosis at altitude: impact on air travel. Eur Respir J 2005; 25:718–724.
Anthea Brincat & Neville Azzopardi
Proton pump inhibitors (PPIs) are widely used in the management of upper gastrointestinal disorders. In recent years, concerns have been raised on the potential adverse effects of long-term PPI use. This article reviews the published evidence of the effect of long-term PPI use on the absorption of minerals and vitamins, risk of infections, chronic kidney disease and dementia.
Proton pump inhibitors (PPIs) are amongst the most commonly prescribed drugs globally, widely used for the prevention and treatment of acid-related disorders such as gastroesophageal reflux disease and peptic ulcer disease. Studies have however, shown that PPIs are often overprescribed or used inappropriately, with 25% - 70% of patients taking these drugs without having an appropriate indication.1 Although PPIs are well tolerated and have been approved for long-term use, concern and evidence on the potential long-term adverse effects are increasingly emerging. This article reviews published information on adverse effects associated with long-term PPI use.
Absorption of Vitamins and Minerals
PPIs block the hydrogen-potassium adenosine triphosphatase enzyme system of the gastric parietal cell, leading to inhibition of gastric acid secretion. This in turn, can lead to decreased absorption of minerals such as calcium, magnesium and iron as well as vitamins such as vitamin B12.
Gastric acid suppression by PPIs has been postulated to result in altered calcium metabolism, causing low bone density and an increased risk of fractures. The mechanism is related to both decreased absorption of calcium compounds in the presence of achlorhydria and primary hyperparathyroidism. The latter results from parathyroid hyperplasia secondary to the hypergastrinaemia caused by profound acid suppression.2 Several studies have investigated the association of PPIs to fracture risk; however the results have been inconsistent. The latest meta-analysis of observational studies, published in 2016, has shown that PPI use modestly increased the risk of hip, spine, and any-site fracture, but with no evidence of duration effect in subgroup analysis.3 Thus, in patients with increased risk of bone fractures, caution should be exercised when prescribing long term PPIs. Adequate dietary calcium intake with vitamin D and calcium supplementation should be considered, ideally in forms that are not influenced by gastric acid for absorption, such as calcium citrate.2,4
Iron and vitamin B12 absorption can be hindered by the low gastric acid levels produced by PPIs. Dietary iron is present in food as non-haem (66%) or haem iron (32%). Gastric acid assists food sources containing non-haem iron to dissociate and to solubilize the iron salts. These salts can then form complexes with sugars and amines, facilitating absorption.5 The data on the effect of PPIs on iron absorption is inconsistent. There are case reports showing iron deficiency anaemia which resolved when PPI therapy was stopped6 and a retrospective cohort study showing a significant decrease in haemoglobin in PPI users.7 Patients with hereditary haemochromatosis were shown to require less frequent phlebotomies when given PPIs.8 On the other hand, two small studies did not show any significant change in iron levels in patients on short or long-term PPIs9,10 whilst a cohort of patients with Zollinger-Ellison Syndrome who received treatment with PPIs for over 10 years did not demonstrate a clinically significant iron deficiency.11 As yet, there are no recommendations to monitor patients on long-term PPI therapy for iron deficiency anaemia and patients shown to be anaemic should be investigated as per published guidelines.
Vitamin B12 is a protein-bound vitamin that requires the presence of gastric acid and pepsin for it to be released in the stomach.12 Once again, studies have shown conflicting data with a recent, large, case-control study showing that the use of PPIs for two years or more was significantly associated with a new diagnosis of vitamin B12 deficiency.13 On the other hand, a cross-sectional study failed to show a significant difference in serum B12 levels in patients on PPIs, compared to their partners who were not on PPIs14. In a systematic review, the authors concluded that PPI therapy does not statistically affect the absorption of vitamin B12.5
In 2011, the FDA released a warning that long-term PPI use may cause hypomagnesaemia, including clinically serious adverse events. In approximately one-quarter of the cases reviewed, magnesium supplementation did not improve the low magnesium level and the PPI had to be discontinued. Whilst the true incidence of PPI-induced hypomagnesaemia is unknown, FDA recommends checking magnesium levels periodically in patients expected to be on prolonged PPI treatment or who take PPIs with other medications that may cause hypomagnesemia (such as diuretics) or digoxin.4
Gastric acid secretion is part of the local defence system against orally ingested pathogens and its suppression could, theoretically, lead to an increased risk of enteric infections. In addition, a twin study has shown a significant impact of PPIs on the gut microbiome.15
Infection with Clostridium difficile is of particular importance due to its morbidity. A meta-analysis of 42 observational studies has shown a probable association between PPI use and incident and recurrent Clostridium difficile infection.16 This resulted in the FDA issuing a safety announcement on the increased risk in PPI users of Clostridium difficile-associated diarrhoea, especially in elderly patients with chronic underlying medical conditions or on broad spectrum antibiotics.4 A systematic review has also shown that PPI use increases patient susceptibility to other enteric infections such as Salmonella, Campylobacter jejuni and small intestinal bacterial overgrowth.17
Long-term PPI treatment has also been linked to pneumonia. The mechanism with this association may be due to upper gastrointestinal bacterial overgrowth, resulting in an increased susceptibility to respiratory infections by potential micro-aspiration or translocation into the lungs. Data is inconsistent, with some recent meta-analyses suggesting that PPI use is associated with an increased risk of both community and hospital-acquired pneumonia18 and others failing to show an association.19
Over the years, concerns have been raised about the adverse renal effects of PPIs, with acute interstitial nephritis being the most frequently observed acute kidney damage in PPI users. The proposed mechanism is thought to be secondary to deposition of PPIs or their metabolites in the kidney’s tubulo-interstitium compartment and direct stimulation of an immune response.20 Three large population-based studies in Canada, the United States and New Zealand have all shown a higher risk of acute interstitial nephritis in patients on PPIs compared to controls. In some cases, this acute injury goes unrecognized and therefore uncorrected. While most patients recover kidney function, many are left with some level of chronic kidney injury.12,20 Several studies have shown an association of PPI use with chronic kidney disease.21 Caution should therefore be exercised when prescribing PPIs to patients who have other risk factors for renal disease and patients on long-term treatment should have their renal function monitored.
PPIs were shown to lead to higher levels of amyloid-beta in the brains of mice in a manner similar to the extracellular deposition of amyloid-beta peptides seen in the pathogenesis of Alzheimer’s disease. This lead to the hypothesis that PPI use can be associated with an increased risk of dementia. A systematic review looking at 11 studies showed a positive association between PPI use and dementia (three out of four studies) or acute cognitive impairment; however, the authors pointed out several methodological problems and conflicting results.22 Further longitudinal studies are needed to confirm this association.
Although PPIs are safe and effective drugs, their long-term use carries potential risks. As with all medications, there should be a clear indication when prescribing PPIs, with the lowest effective dose being used. It is recommended to weigh the benefits of PPI therapy against the risks, especially in patients with multiple co-morbidities and in the elderly. As clinical situations may change over time, patients should be regularly reviewed as to whether acid suppression is still required.
- Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors.BMJ 2008; 336(7634):2-3.
- Yang Y-X. Chronic PPI Therapy and Calcium Metabolism.Current gastroenterology reports 2012; 14(6):473-479.
- Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 2016; 27:339-347.
- US Food and Drug Administration (FDA). FDA Drug Safety Communication. Available from: http://www.fda.gov/Drugs/default.htm.
- Ito T, Jensen RT. Association of Long-term Proton Pump Inhibitor Therapy with Bone Fractures and effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium.Current gastroenterology reports 2010; 12(6):448-457.
- Sharma V, Brannon M, Carloss E. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia.South Med J 2004; 97:887–889.
- Sarzynski E, Puttarajappa C, Xie Y, Grover M, Laird-Fick H. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci 2011; 56:2349.
- Hutchinson C, Geissler C, Powell J, Bomford A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis.Gut 2007; 56:1291–1295.
- 9. Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol 1992; 14(4):288-92.
- 10. Tempel M, Chawla A, Messina C, Çeliker MY. Effects of Omeprazole on Iron Absorption: Preliminary Study. Turkish Journal of Hematology 2013;30(3):307-310.
- Stewart C, Termanini B, Sutliff V, et al. Iron absorption in patients with Zollinger–Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998;12:83-98.
- Eusebi LH,Rabitti S, Artesiani ML, et al. Pump Inhibitors: Risk of Long-term Use.Journal of Gastroenterology and Hepatology. 2017. (Epub ahead of print).
- Lam JR, Schneider JL, Zhao W, Corley DA. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. JAMA 2013; 310(22):2435-2422.
- Den Elzen WP, Groeneveld Y, De Ruijter W, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Alimentary Pharmacology & Therapeutics 2008; 27:491–497.
- Jackson MA, Goodrick JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016; 65:749–56.
- Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. American Journal of Gastroenterology 2012; 107(7):1011-1019.
- Bavishi C, DuPont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Alimentary Pharmacology & Therapeutics 2011; 34:1269–1281.
- Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of Community-Acquired Pneumonia with Outpatient Proton-Pump Inhibitor Therapy: A Systematic Review and Meta-Analysis. PLoS ONE 2015; 10(6):e0128004.
- Filion KB, Chateau D, Targownik LE, et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis.Gut 2014; 63(4):552-558.
- Moledina DG, Perazella MA. PPIs and kidney disease: from AIN to CKD. J Nephrol 2016; 29:611.
- Arora P, Gupta A, Golzy M, et al. Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.BMC Nephrology 2016; 17:112.
- Batchelor R, Gilmartin JF, Kemp W, Hoppler I, Liew D. Dementia, cognitive impairment and proton pump inhibitor therapy - a systematic review. J Gastroenterol Hepatol 2017 Jan 27. (Epub ahead of print).
Treatment with a pharmaceutical formulation of cannabidiol alongside other anti-epilepsy treatments helped to reduce the number of drop seizures – seizures which involve sudden falls due to loss of muscle tone – in people with Lennox-Gastaut syndrome who did not respond to previous treatment, according to a phase 3 randomised clinical trial published in The Lancet.