Ketamine for Acute Painful Crisis in Sickle Cell Disease Patients
Ketamine for Acute Painful Crisis in Sickle Cell Disease Patients
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.
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.