Ketamine for Acute Painful Crisis in Sickle Cell Disease Patients

Ketamine for Acute Painful Crisis in Sickle Cell Disease Patients: Prospective Randomized Control Trial

Investigators hypothesize that administration of ketamine for pain relief in sickle cell patients with vaso-occlusive crisis early on will lead to a more rapid improvement in pain score and less narcotic requirement.

Sickle cell disease is an inherited hematological disorder where the shape of red blood cells (RBC) is altered into a sickle-like cells resulting in red blood cell destruction and therefore anemia and other complications. It's a widely spread condition in African American population as well as the Southern and Eastern Provinces of Arabian Peninsula. Acute painful episodes are a very common complication of the disease process, mainly thought to be a result of tissue ischemia due to occlusion of the microcirculation with clusters of sickled RBC(1). This usually involves long bones or spine but can involve other areas. Acute painful crises can also be precipitated by cold exposure, dehydration, infection, hypoxia, acidosis, hypercarbia, or in some cases it is not related to a specific trigger. This condition puts the patient in severe pain requiring multiple Emergency Department (ED) visits and sometimes admission to the hospital. Currently the mainstay of therapy for acute painful crises is hydration and IV analgesia (2). This makes pain control challenging for the emergency physician as management of acute painful crises requires multiple doses of intravenous (IV) opioids. A retrospective study of 19 patients and 57 visits showed that accumulative dose of IV morphine ranged between 4 milligram (mg) and 26.7 (0.05-0.5 mg/kg) during 70% of the visits. 50% of the patients were admitted after less than 3 hours of ED treatment, 28% of the discharged patients returned to the ED within 3 days (3). Also, as other chronic pain patients, sickle cell disease patients develop opioid induced hyperalgesia (OIH) leading to activation of N- methyl D Aspartate receptors (NMDA) (1). The use of ketamine, a non-competitive NMDA receptor antagonist, may have the potential to modulate the OIH through impaired sensitization of spinal neurons to nociceptive stimuli and may, therefore, impede development of and blunt neuropathic pain. Extensive search of literature databases showed few published reports and retrospective studies including few patients which have addressed the use of low-dose ketamine in the management of acute painful crises in sickle cell disease (SCD) (4-6). A retrospective study (5) included 5 children and adolescents received a low-dose ketamine infusion for the treatment of sickle cell-related pain demonstrated reduced pain scores in 40% of patients and significant reduction in opioid utilization in only 20% of patients. However, that report was retrospective in nature, non-powered, and included few patients. A recent Canadian retrospective study including 9 adult and adolescent patients demonstrated statistically significant reduced cumulative morphine consumption (146±16.5 mg/day vs. 112.±12.2 mg/day) and pain scores after adding intravenous ketamine in patients with painful sickle cell crises (7). Similarly, another American investigators reported decreased opioid consumption with infusing low-dose ketamine as an adjuvant analgesic in 30 patients presented with sickle cell disease with vaso-occlusive crisis (VOC), that study was retrospective (2). Moreover, in year 2017, a prospective, randomized, double dummy trial was done comparing the adverse effects and analgesic efficacy of low-dose ketamine for acute pain in the ED either by single intravenous push or short infusion. This study shows that low-dose ketamine administered as short infusion is related with a significantly lower rates of feeling of unreality and sedation with no difference in analgesic efficacy in comparison to intravenous push (8) To the best of investigator's knowledge, there is no large, prospective, comparative, controlled clinical trial investigated in the addition of low-dose ketamine in shortening the ER stays and improving the quality of analgesia in patients with VOC. Sample Size A data obtained from a pilot study included 10 patients who received either morphine or ketamine showed that the mean and SD of pain visual analogue score (VAS) at 1-hour following administering the study drug among patients presented with sickle-cell VOC were (Morphine 6.5 ± 3.41565, Ketamine: 1.6667 ± 1.52753). An a priori power analysis indicated that a sample size of 220 patients is sufficiently large to detect a mean difference in the pain VAS of 1.5 that would have a clinical importance, with a type-I error of 0.05 and a power of 90%. Additional patients (20%) will be added for a final sample size of 264 patients to compensate for those dropping out during the study. Interim Analysis An independent safety committee will perform three interim analyses on information time 25% (55 patients), 50% (110 patients) and 75% (165 patients). Data evaluation at each interim analysis will be based on the alpha spending function concept, according to Lan and DeMets, and will employ O'Brien-Fleming Z-test boundaries, which are very conservative early in the trial. For the first interim analysis the efficacy stopping rule would require an extremely low P value (P< 0.000015). For the second interim analysis P< 0.003 will be taken as efficacy stopping rule. For the third interim analysis P< 0.02 will be taken as efficacy stopping rule. Investigators will be kept blind to the interim analysis results.

Triple-blind study. The study solution will be prepared in identical 100-ml Normal Saline bags by the research nurse

Patients will receive standard dose of morphine (0.1 mg/kg) in 100 ml normal saline (NS) infused over 30 minutes in addition to standard IV hydration.

Patients will receive low dose ketamine 0.3 mg/kg in 100ml normal saline (NS) infused over 30 minutes in addition to standard IV hydration

Patients will receive standard dose of morphine (0.1 mg/kg) in 100 ml normal saline infused over 30 min in addition to standard IV hydration.

Patients will receive low dose ketamine 0.3 mg/kg in 100ml N.S. infused over 30 min in addition to standard IV hydration

IV hydration as per our institutional protocol (Lactated Ringer's or NaCl 0.9% solution will be infused at a rate of 2-3 ml/kg/h)

Improvement of pain scores using Numerical Pain Rating Score (NPRS) (0: no pain, 10: worst imaginable pain)

flushing, hypotension, altered mental status, itching, paraesthesia, respiratory depression, dizziness, nausea, vomiting

Inclusion Criteria: Known diagnosis of SCD based on sickle cell tests and hemoglobin electrophoresis. Age 18 to 60 years Acute onset of painful crises, defined as having an onset within 7 days Exclusion Criteria: Pregnancy Breast-feeding Altered mental status Body mass index greater than 40 kg/m2 Patients with significant neurological disease Seizures Acute head injury Acute eye injury Patients with high intra-cranial tension Patients with known psychiatric disorders Patients with significant cardiac diseases Arrhythmias Patients with significant pulmonary diseases rather than acute chest syndrome Patients with significant renal disease (BUN/creatinine ratio < 25) Patients with significant hepatic disease (Child Pugh class B or C) Patients with significant endocrine disease Known allergy to phencyclidine derivatives Known allergy to ketamine Known allergy to morphine Sepsis Septic shock Patients required circulatory support Patients required ventilatory supports Alcohol abuse Drug abuse Patients with chronic pain status unrelated to SCD Patients receiving anti-convulsant medications Patients receiving anti-psychiatric medications. Patients with communication barriers.

Emergency and Critical Care Medicine Consultant Director, Critical Care Medicine Department Medical Director, King Fahad Hospital of the University Associate Professor - College of Medicine Imam Abdulrahman Bin Faisal University - (Dammam University)

Alshahrani MS, Asonto LP, El Tahan MM, Al Sulaibikh AH, Al Faraj SZ, Al Mulhim AA, Al Abbad MF, Al Nahhash SA, Aldarweesh MN, Mahmoud AM, Almaghraby N, Al Jumaan MA, Al Junaid TO, Al Hawaj FM, AlKenany S, ElSayed OF, Abdelwahab HM, Moussa MM, Alossaimi BK, Alotaibi SK, AlMutairi TM, AlSulaiman DA, Al Shahrani SD, Alfaraj D, Alhazzani W. Study protocol for a randomized, blinded, controlled trial of ketamine for acute painful crisis of sickle cell disease. Trials. 2019 May 27;20(1):286. doi: 10.1186/s13063-019-3394-4.