Treatment of acute painful crisis of sickle cell disease remains a challenge in the management of SCD patients. It is also equally important to recognize a pain crisis early, correct the inciting causes, control pain and prevent further complications [14
]. There is no protocol yet for management of pain crisis in SCD in spite of advancement in pain management. The physicians and hematologists hesitate to use narcotic drugs for the obvious reason of addiction, tolerance and side effects [15
]. In most patients, a pain crisis resolves within five to seven days [17
According to US Department of Health and Human Services guidelines on the management of SCD, self-reporting of pain is the most reliable indicator of the presence and intensity of pain [18
]. The VAS is an easy to use, reliable pain assessment tool in patients older than 5 years [19
] and has been intensely validated in patients with SCD [20
This present study is the first report on nitric oxide inhalation efficacy and safety in sickle cell acute pain crisis in Indian patients having Arab-Indian haplotype. Similar study has been done in the past in American patients [21
]. The observation is limited to acute pain only. The magnitude of change in VAS pain scores observed in this study was similar to that of earlier report [22
It also aims at gathering information regarding the safety of NO therapy in acute VOC in SCD. There were no episodes of hypotension
, clinically significant decrease in sp02
or significant increase in methemoglobin level (<5%) indicating there by that nitric oxide inhalation for 6 to 8 hrs is safe.
The results of this small preliminary study with short treatment duration provide strong evidence of the safety and efficacy of nitric oxide inhalation as evidenced by reduction of VAS score after 3 to 4 hrs. There was no toxicity observed during or after inhalation of Nitric oxide. However, 2 patients again were readmitted to the hospital for nitric oxide inhalation within a short time indicating that it is a temporary relief and may need reinstitution of nitric oxide inhalation depending upon the severity of vaso-occlusion. The limitations of this study include the relatively small sample size.
Thus our data suggest that inhaled NO at 80 ppm for 6 to 8 hrs is well tolerated. Without any toxicity or side effect as evidenced by no significant rise in methemoglobin level in blood and also unchanged laboratory parameters.
Oxygen therapy is often used in the management of VOC, despite lack of evidence supporting the effectiveness of these measures in all patients [23
]. Oxygen may also suppress erythrocyte production, depress reticulocytosis and cause rebound sickle cell crisis on discontinuation of therapy when arterial oxygen tension is raised above the normal range [25
]. Nitric oxide inhalation has been reported to increase the oxygen affinity of sickle erythrocytes. Also, inhaled NO reacts with hemoglobin in SS and AA individuals, resulting in significant increases in NOX compounds and mild elevations in methemoglobin. The level of nitrosylation may provide a mechanism to augment NO delivery to the microvasculature and possibly improve micro vascular perfusion [26
However, a multicenter, randomized controlled phase 2 trial from USA reported that inhaled nitric oxide gas had no effect on the time to VOC resolution or any of the planned secondary analyses, including length of hospitalization, change in VAS score and total opioid use.21 But, in the same study the fact that patients in INO (Nitric oxide inhalation) group used less narcotics than those in the placebo group may suggest a clinically significant effect of iNO. There was a modest but not statistically significant trend toward shorter hospitalization in patients with iNO group. It is observed that they have given NO gas 80 ppm for 4 hrs only where as ours is 6 hrs.
In addition, we feel that this difference may be due to several other factors like genotype of sickle cell disease cases, the amount of nitric oxide deficiency in individual patients, the amount of Hb F in the patients etc. It is well known that cases of sickle cell anaemia homozygous patients do have nitric oxide deficiency due to intravascular hemolysis which lowers the level of nitric oxide [27
]. Beneficial effect of Nitric oxide inhalation in Acute chest syndrome of SCA cases has also been reported [28
]. The mechanism proposed is dilation of pulmonary vascular bed reducing after load on the right ventricle, redistributing pulmonary blood flow to better ventilated areas of lung and potentially reducing sickling in the lung. Inhibition of platelet aggregation has been suggested as an additional beneficial effect of nitric oxide in respiratory failure.
Thus it can be concluded that inhaled ‘NO’ as potent vasodilator, may play a critical role in the treatment of VOC of Sickle Cell Disease and provide effective therapy for these patients avoiding the use of narcotic drugs.