INTRODUCTION

Sickle cell disease (SCD) is a hereditary hematologic disorder in which deoxygenated hemoglobin polymerizes, resulting in the sickle-like shape of red blood cells. These rigid, misshapen cells trigger vasoocclusion in the microcirculation, resulting in tissue ischemia. In addition, damage to the red blood cell membrane causes chronic hemolytic anemia.

Vasoocclusive crisis (VOC) is the most common complication of SCD and is associated with severe pain that may recur frequently, requiring emergency department (ED) visits and hospitalization. Patients who are frequently hospitalized because of painful VOC are at a higher risk of early death.

The cost of hospital admission for SCD patients is on the rise. In 2017, the public heath registry recorded approximately 14,000 individuals living with SCD in the UK; indicating that one in 4600 people living in the UK have SCD.In the US, a study conducted in 2009 revealed that SCD affected close to 100,000 individuals and cost more than $1.1 billion.

Although SCD is prevalent in Saudi Arabia, studies show significant variations in its prevalence across the country. The occurrence in the Eastern province is 145 cases/10,000 residents, 24 cases/10,000 in the Southern Province, 12 cases/10,000 in the Northern Province, 6 cases/10,000 in the Western and Central Provinces, respectively.

Standard therapy for VOC includes intravenous (IV) hydration and opioid analgesia. Although existing evidence supports the use of opioid therapy for the treatment of VOC,treating physicians often encounter challenges when attempting to balance the analgesic and adverse effects of opioids. A cross-sectional survey of 721 ED physicians found that emergency physicians who attend to more than one SCD patient per week were inclined to have negative attitude toward SCD patients and were less likely to redose opioids within 30 min for inadequate analgesia. Commonly reported side effects of opioids are drowsiness, nausea, abdominal pain, confusion, and respiratory depression with variable incidence.Similar to other patients receiving treatment for chronic or recurrent pain, 
SCD patients may experience opioid-induced hyperalgesia, an enhanced pain response owing to the activation of the N-methyl-d-aspartate (NMDA) receptors.

Ketamine, a noncompetitive NMDA receptor antagonist, may modulate opioid-induced hyperalgesia by impairing the sensitization of the spinal neurons to nociceptive stimuli. Ketamine acts on glutamate and NMDA receptors, which modulate the peripheral pain sensitization process along the pain pathways.
Ketamine is also proposed to affect neural plasticity on the NMDA and the spinal pathway by preventing the transmission of the generated stimuli toward the central nervous system. Thus, ketamine may reduce pain. Because patients with long-term exposure to opioid therapy are prone to drug-related dependency, the administration of ketamine therapy may minimize this.To date, only one randomized clinical trial (RCT) that enrolled children with VOC who were randomly administered ketamine or morphine has been published which found that ketamine was noninferior to morphine at reducing pain scores, with authors reporting increased adverse events in the ketamine arm, although they were mild and transient. Presently, the effect of adding ketamine to the treatment regimen for adults with VOC is unclear. Furthermore, there are no published RCTs investigating the effect of low-dose ketamine on pain scores in adults with VOC. Thus, we opted to perform a large RCT to evaluate this therapy.

METHODS

Trial design

This study was a parallel-group, prospective, randomized, blinded, pragmatic, controlled trial that sought to evaluate the efficacy and safety of single-dose ketamine infusion in addition to the usual care relative to those of morphine, for the management of sickle VOC. Ethical approval was granted by the institutional review board at Imam Abdulrahman Bin Faisal University. Between January 2018 and February 2019, patients were recruited at the ED of King Fahd Hospital, the largest tertiary academic international accredited hospital in the Eastern Province of Saudi Arabia; this hospital has an average number of ~180,000 ED patient visits per year.

We registered the trial protocol online (Clinicaltrials.gov registration NCT03431285) and, subsequently, published the full protocol. All authors affirm the accuracy and completeness of the data and adherence to the approved protocol.

Participants

We enrolled adults 18 years and older with SCD, confirmed hemoglobin electrophoresis results consistent with any SCD genotype (homozygous hemoglobin S [HbSS], compound heterozygous S with C [HbSC], or sickle beta thalassemia [HbSβ] or any other genotypes), and numeric pain rating scale (NPRS) score > 5, who presented with acute sickle VOC with onset within the 7 days prior to ED visit. Exclusion criteria were pregnant or breast-feeding women, patients with body mass index of >40 kg/m2, known neurological disease, seizures, acute head or eye injury, psychiatric disorders, known cardiac diseases, known pulmonary diseases besides acute chest syndrome, renal disease, chronic liver disease, allergic to the study drugs, sepsis or septic shock, need for circulatory or ventilatory support, alcohol or drug abuse, or known chronic pain that is unrelated to SCD.

Randomization, blinding, and treatment

Patients were randomized using a block size of six into online, computer-generated program, which concealed randomization and treatment allocation. Patients were assigned to a 1:1 ratio to receive and either a single low-dose of ketamine (0.3 mg/kg) in 100 ml of normal saline or a standard dose of morphine (0.1 mg/kg) in 100 ml of normal saline. All patients received standardized IV hydration. Participants, health care providers, data collectors, and outcome assessors were blinded to the treatment allocation. To ensure blinding, we used 100-ml normal saline bags with similar appearance and consistency.

Study procedures

Upon eligibility confirmation and written consent, demographics, NPRS, Richmond Agitation Sedation Scale (RASS), and clinical variables (pulse rate, respiratory rate, blood pressure, and oxygen saturation) were collected by trained study nurses. Normal saline or Ringer’s lactate was administered at a maintenance rate through a peripheral IV line, as per pre-designed pathway (Appendix S1, available as supporting information in the online version of this paper, which is available at http://onlinelibrary.wiley.com/doi/10.1111/acem.14382/full). In addition, prior to administering the study intervention, ED physicians were allowed to prescribe a nonnarcotic preanalgesia of either IV paracetamol 1-g infusion or nonsteroidal anti-inflammatory drugs, either lornoxicam 8–16 mg IV or diclofenac 75-mg intramuscular injection. The choice of analgesic was based on the treating physician’s discretion. At 30 min following the initial administration of the nonopioid analgesia, patients with NPRS score above 5 were enrolled in the study.

End points

The primary outcome was pain rated by NPRS. Patients blinded to the study drug were asked to rate their pain at the initial assessment, and the score was recorded by the bedside nurse every 30 min for a minimum of 30 min and a maximum of 180 min. Pain was measured on a scale from 0 (no pain) to 10 (the worst pain).

Secondary outcomes were the cumulative dose of opioids administered including the intervention dose, the length of ED stay (defined as the time from the start of administration of the study medication to discharge home or admission), hospital admission rate, difference in RASS scores, patient’s hemodynamic parameters, heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SpO2), and drug-related adverse effects.

Blinded attending physicians in the ED performed patient management and administered rescue pain medications at their discretion. Patients were discharged after a minimum of 120 min if they met the predefined criteria described earlier. Patients with an NPRS score > 5 were admitted to the hospital within a maximum 180 min.

For the administration of the study drugs, the treating team adhered to the standard practice policies and procedures for administering high-alert medications according to The Joint Commission international standards.35 Patients were also monitored by the bedside nurse to identify any ketamine or morphine-related adverse effects.