Can inhaled nitric oxide relieve pain crises in people with sickle cell disease and does it have other beneficial effects (such as lessening the severity of pain, shortening hospital stays, or decreasing how often crises happen again) or any harmful effects?
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 like a crescent (or a sickle, a tool with a curved blade). The abnormally shaped cells easily become stuck in blood vessels, which can cause episodes of severe pain known as 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, a gas that can relax the blocked blood vessels so they can widen and allow the sickled cells to pass. We wanted to find out whether inhaled nitric oxide is effective in relieving pain in people with sickle cell disease.
The evidence is current to 1 September 2021.
We 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, aside 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 placebo (dummy treatment, i.e. room air) which does not provide pain relief. Participants were assigned to one or the other treatment group at random. The treatments lasted for four hours in two trials and eight hours in the third trial.
Only one large trial (150 participants) reported time until the pain stopped, finding no difference 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 readmission 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; however, 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 there were no data that could be analysed. Two trials reported the average duration of stay in hospital: in the large trial those who were given room air had a shorter stay, whilst the smaller trial conducted at the children's hospital reported a shorter stay in those treated with inhaled nitric oxide. Only the larger trial reported on harmful effects of nitric oxide, finding little or no difference between treatment groups.
We could not combine the available data from the three included trials due to differences in the reporting of outcomes. As a result, the currently available evidence is not enough to give a clear 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.
Certainty of the evidence
We judged the evidence that could be analysed to be of low certainty. We believe that the results in this review were affected because not all planned outcomes were reported in two trials, and the trials were small. Furthermore, the pharmaceutical industry financed the smaller adult trial, which should be considered when considering the results of this trial.
The currently available evidence is insufficient 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 standardised manner.
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 subject of controversy; hypotheses have been made suggesting a beneficial response due to its vasodilator properties, yet no conclusive evidence has been presented. This review aimed to evaluate the available randomised controlled studies addressing this topic.
To capture the 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 relevance, robustness, and validity of the treatment to better guide medical practice in the fields of haematology and palliative care (since the recent literature seems to favour the involvement of palliative care for such people).
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register. We searched for unpublished work in 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. The most recent search was conducted on 1 September 2021. We also searched ongoing study registries on 19 November 2021.
Randomised and quasi-randomised trials comparing inhaled nitric oxide with placebo for treating pain crises in people with sickle cell disease.
Two review authors independently assessed trial quality and extracted data (including adverse event data), with any disagreements resolved by consulting a third review author. When the data were not reported in the text, we attempted to extract the data from available tables or figures. We contacted trial authors for additional information. We assessed the certainty of the evidence using the GRADE criteria.
We included three trials involving a total of 188 participants in the review. There were equal numbers of males and females. 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 parts per million (ppm)) to placebo (nitrogen gas mixed with oxygen or 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, we had concerns about risk of bias for the remaining two trials due to their 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, reporting the remaining results narratively.
Evidence from one trial (150 participants) suggested that inhaled nitric oxide may not reduce the time to pain resolution: 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-certainty 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 return to the emergency department (risk ratio (RR) 0.73, 95% CI 0.31 to 1.71) and rehospitalisation (RR 0.53, 95% CI 0.25 to 1.11) (150 participants; low-certainty 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.
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. Two trials reported the median duration of hospitalisation: in the largest trial the placebo group had the shorter duration, whilst 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, and dysphagia and a drop in haemoglobin were each reported in 1 out of 75 participants in the inhaled nitric oxide group) (low-certainty evidence).