Ketamine Infusion Therapy for the Management of Acute Pain in Adult Rib Fracture Patients

Phase 4

Completed

Conditions: Rib Fractures
Wounds and Injuries

Interventions: Drug: Placebo
Drug: Ketamine
Procedure: Intercostal Nerve Block
Drug: Acetaminophen
Drug: Ibuprofen
Drug: Pantoprazole
Drug: Methocarbamol
Drug: Opioid

Registration Number: NCT02432456

Lead Sponsor: Medical College of Wisconsin

Brief Summary: This study will evaluate the effectiveness of ketamine infusions in the management of acute pain resulting from broken ribs suffered following a blunt trauma. Half of patients will receive the institutional standard of care and a placebo infusion (no active medication). The other half of patients will receive the institutional standard of care and a ketamine infusion. All subjects and staff will be blinded as to whether they are receiving placebo or ketamine.

Detailed Description: A prospective randomized, double blinded trial of ketamine use in adult and elderly blunt trauma patients with associated rib fractures admitted to the trauma service will be conducted. Examples of blunt mechanisms include assault, falls, motor vehicle collisions, motorcycle crashes, motor vehicle pedestrian collisions, crush injuries, and bicycle accidents. The experimental arm of the trial will receive ketamine infusion therapy while the control arm receives saline placebo infusions at an equivalent rate. All patients will be managed with adjunct therapy including opiates in accordance with the institutional thoracic trauma protocols. Two separate trials based on patient age are included in this study. Elderly rib fracture patients are certainly of interest but will be evaluated as a distinct entity given the discrete differences in the complications of rib fractures and the goals of therapy.

All blunt trauma patients with associated rib fractures will be screened. All patients will be enrolled into the institutional standard thoracic trauma pathway. All individuals will undergo Intercostal Nerve Block (ICNB) in the Emergency Department or on admission to the Intensive Care Unit. In addition to scheduled medications per institutional thoracic trauma protocols, all patients will receive adjunct opiate therapy. Patients will be screened by the clinical and pharmacy staff following the diagnosis of rib fractures for eligibility. Patients enrolled into the trial will be randomized into either the experimental or control arm of the trial. The Investigational Drug Services (IDS) department will randomize all enrollees and handle administration of all trial drugs. The infusate will be mixed by the IDS department and all bags will be labeled "Ketamine / Placebo." The IDS department will have unique bag identifiers, which will allow them to identify which bags have active ketamine and which are placebo in case of emergency.

Patients will be randomized in a 1:1 fashion for experimental and control arms. Those enrolled in the experimental arm will receive early ketamine infusion therapy at a fixed infusion rate. For those enrolled in the adult trial the infusion rate will be 2.5 mcg/kg/min while those in the elderly trial will receive infusions at 2.0 mcg/kg/min. All ketamine infusions will be calculated based on ideal body weight (IBW), unless actual body weight is less than ideal. IBW will be calculated for males as 50kg + 2.3\*(number of inches above 5 feet) and for women as 45.5kg + 2.3\*(number of inches over 5 feet). Patients randomized to the control arm will receive placebo saline solution at an equivalent rate. Time zero will be defined as the time at which the "ketamine / placebo" infusion is begun. For inclusion in the trial, initiation of ketamine / placebo infusions must take place within 6 hours of presentation to Froedtert Memorial Lutheran Hospital (FMLH). Ketamine infusion therapy will be continued for 48 hours. At 6-8 hours post-ICNB all subjects will be assessed for need for repeat ICNB. Need for repeat ICNB will be defined by a thoracic specific numeric pain score greater than seven. Between eight and ten hours post-ketamine infusion initiation, subjects who have thoracic specific pain scores above seven will be evaluated for epidural placement by the Regional Anesthesia and Acute Pain Service.

A subject will be allowed to remove himself/herself from the trial or be un-blinded should he/she, pharmacy, anesthesia, and/or surgical staff deem it medically necessary. Medical necessity would be determined by inability to treat the patient appropriately without knowledge of trial assignment; otherwise the assumption of treating staff will be all patients have received ketamine. All adverse events will be recorded and if necessary subjects will be un-blinded in the event of a serious adverse event. The trauma and anesthesia teams along with the inpatient clinical pharmacists will monitor all trial patients for any adverse event trends. Patients will be followed through the time of discharge.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 153

Inclusion Criteria

age greater than 18 years
rib fractures following recent trauma with admission to Froedtert Memorial Lutheran Hospital

Exclusion Criteria

history of adverse reaction / intolerance to ketamine therapy
elevated intracranial pressure
ischemic heart disease defined as active acute coronary syndrome
severe, poorly controlled hypertension (Systolic Blood Pressure > 200 mmHg or Diastolic Blood Pressure > 100 mmHg)
current opiate agonist/antagonist therapy
concurrent use of monoamine oxidase inhibitors (MAOIs)
chronic pain or opioid tolerance defined as > 3 weeks of >30mg oral morphine equivalents per day
current substance abuse with opiates (prescription and/or heroin) or ketamine
Glasgow Coma Scale <13
Intubation on arrival or need for urgent intubation on arrival
inability to delineate pain and/or appropriately communicate with staff
history of psychosis
three or more psychotropic medications
active delirium
glaucoma
pregnancy
prisoners

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ketamine Infusion	Intercostal Nerve Block	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Placebo	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Intercostal Nerve Block	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Opioid	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Opioid	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Acetaminophen	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Ibuprofen	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Pantoprazole	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Placebo Infusion	Methocarbamol	Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Ketamine	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Acetaminophen	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Ibuprofen	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Methocarbamol	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Ketamine Infusion	Pantoprazole	Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion. All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.

Primary Outcome Measures

Name	Time	Method
Visual Analog Numeric Pain Score	12-24 hours post infusion	Visual Analog Numeric Pain scores are reported as a single numeric score between 0 and 10. The more severe the pain the higher the number with 10 representing the most severe pain imaginable.

Secondary Outcome Measures

Name	Time	Method
Visual Analog Numeric Pain Score	24-48 hours post infusion	Visual Analog Numeric Pain scores are reported as a single numeric score between 0 and 10. The more severe the pain the higher the number with 10 representing the most severe pain imaginable.
Oral Morphine Equivalent (Narcotic Usage)	24-48 hours post infusion	This is an analysis of the narcotic utilization during the study. Oral Morphine Equivalents is a means of standardizing narcotic utilization given a multitude of different medications are utilized. Medications are standardized to units (milligrams) or oral morphine for a standardized comparison.
Length of Stay	Total Index Hospitalization up to 365 days	Total hospital length of stay in days up to 365 days.
Regional Anesthesia Utilization	Total Index Hospitalization up to 365 days	This is a measure of the Epidural Placement rates. Epidural placement was binary as in patient received or did not receive an epidural infusion catheter for supplemental pain management.
Respiratory Failure	Total Index Hospitalization up to 365 days	Respiratory failure within this trial was defined by the need for unanticipated intubation and/or transfer to ICU for respiratory support.
Hallucination	Total Index Hospitalization up to 365 days	Hallucinations were documented and confirmed by the treating medical team.
Oral Morphine Equivalent (Narcotic Usage) in Severely Injured	Total Index Hospitalization up to 365 days	This is an analysis of the narcotic utilization during the study. Oral Morphine Equivalents is a means of standardizing narcotic utilization given a multitude of different medications are utilized. Medications are standardized to units (milligrams) or oral morphine for a standardized comparison.