We reviewed the evidence about the effects of inhaled nitric oxide for relieving pain crises in people with sickle cell disease.
Sickle cell disease is a condition that affects the red blood cells. Normal red blood cells are round, but in people with sickle cell disease some of the red blood cells can have an abnormal shape. They look like a crescent (or an old-time tool called a 'sickle'). The abnormally-shaped cells easily become stuck in blood vessels which can cause episodes of severe pain called 'pain crises'. The pain can be in the bones, chest, or other parts of the body, and can last from several hours to days.
Painkillers are the main treatment of these pain crises. Another suggested treatment is inhaled nitric oxide, which is a gas that can relax the blocked blood vessels so they can widen and allow the sickled cells to pass. We wanted to evaluate whether inhaled nitric oxide is effective in relieving pain in people with sickle cell disease.
The evidence is current to: March 2018.
The review included three trials with 188 people (equal numbers of males and females) with sickle cell disease who were experiencing a pain crisis. Most participants were adults, except for one trial conducted in a children's hospital where most participants were children over 10 years of age. The trials compared inhaled nitric oxide with a control (room air), which does not provide pain relief, and people were selected for one treatment or the other at random. The treatments in two trials lasted for four hours and in the third trial lasted for eight hours.
Only one large trial (150 participants) reported no difference in the time until the pain stopped between nitric oxide or room air. This trial was also the only trial to report on the frequency of pain crises in the follow-up period and we found little or no difference between inhaled nitric oxide and room air for a return to the emergency department or for re-admission to hospital. All three trials reported pain scores; the larger trial found no difference between nitric oxide or room air at each time-point up to eight hours, but the two smaller trials (38 participants) reported a benefit of inhaled nitric oxide in relieving the pain after four hours, but these trials were small and limited compared to the first trial.
All three trials reported that inhaled nitric oxide had no effect on decreasing the use of painkillers, but did not provide any data we could analyse. Two trials reported the average duration of stay in hospital; in the large trial those who were given room air had a shorter stay, and one of the smaller trials (at the children's hospital) reported a shorter stay in those treated with inhaled nitric oxide. Only the larger trial reported harmful effects of nitric oxide and found that treatment made little or no difference.
We could not combine the available data from the three included trials due to differences in the reporting of outcomes. Therefore, the currently available evidence is not enough to give a definitive answer about the use of inhaled nitric oxide for people with sickle cell disease experiencing a pain crisis.
Future trials, preferably large-scale and long-term, should be carried out to provide strong evidence in this area. Investigators should measure and report outcomes important to patients (e.g. measures of pain and time to pain resolution and amounts of analgesics used) as well as use of healthcare services in a standardised way.
Quality of the evidence
We judged the evidence we were able to analyse to be of low quality. We believe that the the results in this review were affected because not all planned outcomes were reported in two of the trials and the trials were only small. Furthermore, the fact that the pharmaceutical industry financed the smaller adult trial should be considered when looking at the results of this trial.
The currently available trials do not provide sufficient evidence to determine the effects (benefits or harms) of using inhaled nitric oxide to treat pain (vaso-occlusive) crises in people with sickle cell disease. Large-scale, long-term trials are needed to provide more robust data in this area. Patient-important outcomes (e.g. measures of pain and time to pain resolution and amounts of analgesics used), as well as use of healthcare services should be measured and reported in a standardized form.
In people with sickle cell disease, sickled red blood cells cause the occlusion of small blood vessels which presents as episodes of severe pain known as pain crises or vaso-occlusive crises. The pain can occur in the bones, chest, or other parts of the body, and may last several hours to days. Pain relief during crises includes both pharmacologic and non-pharmacologic treatments. The efficacy of inhaled nitric oxide in pain crises has been a controversial issue and hypotheses have been made suggesting a beneficial response due to its vasodilator properties. Yet no conclusive evidence has been presented.
This review aims to evaluate the available randomised controlled studies which address this topic.
To capture the available body of evidence evaluating the efficacy and safety of the use of inhaled nitric oxide in treating pain crises in people with sickle cell disease; and to assess the treatment's relevance, robustness, and validity, in order to better guide medical practice in the fields of haematology and palliative care (since recent literature seems to favour the involvement of palliative care for those people).
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. Unpublished work is identified by searching the abstract books of the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting.
Date of most recent search: 19 September 2019.
We also searched ongoing study registries, date of most recent search: 26 September 2019.
Randomised and quasi-randomised trials comparing inhaled nitric oxide with placebo, or standardized way of treatment of pain crises in people with sickle cell disease.
Two authors independently assessed trial quality and extracted data (including adverse event data). A third author helped clarify any disagreement. When the data were not reported in the text, we attempted to extract the data from any table or figure available. We contacted trial authors for additional information. We assessed the quality of the evidence using the GRADE criteria
We identified six trials, three of which (188 participants) were eligible for inclusion in the review. There were equal numbers of males and females; and most participants were adults, although one small trial was conducted in a children's hospital and recruited children over the age of 10 years. All three parallel trials compared inhaled nitric oxygen (80 ppm) to placebo (room air) for four hours; one trial continued administering nitric oxide (40 ppm) for a further four hours. This extended trial had an overall low risk of bias; however, in the remaining two trials we had concerns about the risk of bias from the small sample size and additionally a high risk of bias due to financial conflicts of interest in one of these smaller trials. We were only able to analyse some limited data from the eight-hour trial and report the remaining results narratively.
The time to pain resolution was only reported in one trial (150 participants), showing there may be little or no difference between the two groups: with inhaled nitric oxide median 73.0 hours (95% confidence interval (CI) 46.0 to 91.0) and with placebo median 65.5 hours (95% CI 48.1 to 84.0) (low-quality evidence). No trial reported on the duration of the initial pain crisis. Only one large trial reported on the frequency of pain crises in the follow-up period and found there may be little or no difference between the inhaled nitric oxide and placebo groups for a return to the ED, risk ratio 0.73 (95% CI 0.31 to 1.71) or for re-hospitalisation, risk ratio 0.53 (95% CI 0.25 to 1.11) (150 participants; low-quality evidence).
There may be little or no difference between treatment and placebo in terms of reduction in pain score at any time point up to eight hours (150 participants). The two smaller trials reported a beneficial effect of inhaled nitric oxide in reducing the visual analogue pain score after four hours of the intervention, but these trials were small and limited compared to the first trial.
Analgesic use was reported not to differ greatly between the inhaled nitric oxide group and placebo group in any of the three trials, but no analysable data were provided. The median duration of hospitalisation was reported by two trials, in the largest trial the placebo group had the shorter duration and in the second smaller (paediatric) trial hospitalisation was shorter in the treatment group.
Only the largest trial (150 participants) reported serious adverse events, with no increase in the inhaled nitric oxide group during or after the intervention compared to the control group (acute chest syndrome occurred in 5 out of 75 participants from each group, pyrexia in 1 out of 75 participants from each group, dysphagia and a drop in haemoglobin were each reported in 1 out of 75 participants in the inhaled nitric oxide group, but not in the placebo group) (low-quality evidence).