Introduction
Background
Acute cyanide poisoning occurs most commonly from smoke inhalation but can also occur from industrial accidents or suicide attempts.Reference Dart1 Many smoke-inhalation victims are treated early in their clinical course with cyanide antidotes, namely hydroxocobalamin.Reference Fortin, Giocanti and Ruttimann2, Reference Borron, Baud and Barriot3 Due to its pigmentation, hydroxocobalamin has been found to cause interferences in many laboratory assays.4–Reference Vest, Renaudeau and Tellal7 Co-oximetry also may be affected by hydroxocobalamin. Two animal studies suggest that hydroxocobalamin may cause false elevations in hemoglobin concentration, methemoglobin, carboxyhemoglobin, and a false decrease in oxyhemoglobin.Reference Denninghoff, Walter and Langa8, Reference Lee, Mukai and Kreuter9
Importance
The Masimo Radical-7 (Masimo Corporation, Irvine, California USA) is a medical device that performs noninvasive oximetry and estimates hemoglobin (Hb) concentration, carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin saturation (O2Hb). Hydroxocobalamin is known to cause alterations in co-oximetry measurements. The effect of hydroxocobalamin on noninvasive oximetry is unknown.
Goals of This Investigation
The effect of hydroxocobalamin on surface-probe oximetry has not been evaluated previously. Therefore, the aim of this investigation was to determine the effect of hydroxocobalamin on noninvasive measurement of hemoglobin indices using the Masimo Radical-7. The study hypothesis was that the administration of hydroxocobalamin would cause variations in Hb, O2Hb, COHb, and MetHb.
Methods
Study Design and Setting
This prospective quantitative study compared surface oximetry readings of Hb, O2Hb, COHb, and MetHb before and after administration of hydroxycobalamin. The study was conducted at Madigan Army Medical Center, a large military teaching hospital located in Tacoma, Washington (USA). Institutional Review Board approval was obtained.
Selection of Participants, Data Collection and Processing
Eligible patients were healthy, male, nonsmoking volunteers age 18 years or older who were unexposed to cyanide. Exclusion criteria included: known anemia, blood dyscrasias, recent exposure to carbon monoxide or cyanide, medications known to induce methemoglobinemia, peripheral arterial disease, hypertension, and hypersensitivity to hydroxocobalamin or cyanocobalamin. Additionally, subjects with a pre-test systolic blood pressure <100 mm Hg were excluded due to potential for poor monitoring performance. Written informed consent was obtained for all subjects.
Methods of Measurement
Study operators were trained on use of the Masimo Radical-7 noninvasive monitor and were proficient in its use prior to initiation of the study. Total hemoglobin (Hb), carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin (O2Hb) readings were obtained using the monitor. The probe was placed on the left fourth finger (ring finger) of each subject's hand and remained in place throughout the study. A baseline Hb, COHb, MetHb, and O2Hb reading was obtained and recorded. Each of the volunteers received 5 g of hydroxocobalamin diluted in 200 cc of normal saline intravenously over 15 minutes in the contralateral upper extremity. Hydroxocobalamin dosing for this study followed the prescribing information from the Cyanokit (Meridian Medical Technologies, Inc., Columbia, Maryland, USA) package insert.4 Demographic data was recorded as well as baseline blood pressure and heart rate. Readings for all hemodynamic and hemoglobin parameters were recorded at 5, 10, 15, 30 and 60 minutes. If values were less than five percent of baseline, the study was terminated at 60 minutes. If values were not less than five percent of baseline at 60 minutes, monitoring was to be extended to semi-hourly monitoring, up to six hours post infusion.
Primary Data Analysis
The primary end point was the difference between pre- and post-infusion readings of CO and MetHb obtained by the noninvasive monitor. Additional readings included Hb, O2Hb, blood pressure, and heart rate. Data were analyzed by calculating the area under the curve (AUC) for each variable and comparing the results to expected values by paired t tests using Excel (Microsoft Corporation, Redmond, Washington, USA). Expected AUC values were calculated by extrapolating baseline values across the entire time period.
Data from the authors’ previous institutional quality assurance testing of the Masimo Radical-7 device for hemoglobin measurements revealed a standard deviation of 1.3 for the difference between probe measurements and laboratory confirmation. Therefore, a conservative estimate of five was chosen for the standard deviation of this protocol. An effect size of four was selected, which was felt to be a clinically significant change for carboxyhemoglobin measurements. Sample size was determined to be 12 with a power of 0.8 and two-sided alpha of 0.05 to detect a difference between pre-infusion and post-infusion measurements.
Results
Initially eight subjects were enrolled. The study protocol was discontinued after one subject experienced sinus bradycardia at 28 bpm with mild light-headedness, which resolved with discontinuation of the infusion. After complete data were available on seven subjects, an interim analysis was performed by the request of the Institutional Review Board to determine if additional subjects would be needed. The mean difference from baseline values with 95% confidence interval and t test of mean difference were: SBP: 11 mm Hg (95% CI, 0-22; P = .051); HR: -9 (95% CI, -15 to -3; P = .01); Hb: -0.1 (95% CI, -0.7 to 0.4; P = .57); O2Hb: 0 g/dL (95% CI, -1 to 1; P = .41); COHb: -1 (95% CI, -3 to 1; P = .25); MetHb: -0.2 (95% CI, -0.3 to 0; P = .03). After reviewing these data, the authors felt that additional subjects would not be justified given a trivial influence on the primary endpoint of COHb and MetHb concentrations.
Discussion
Statistically significant differences were identified for pre- and post-infusion heart rate, blood pressure, and methemoglobin concentration; however the difference in methemoglobin concentration (-0.2%) is unlikely to be clinically significant. No statistically significant differences were observed in hemoglobin, carboxyhemoglobin, or oxyhemoglobin concentrations.
Results of this study suggest that surface oximetry may be a viable alternative to traditional co-oximetry for measurement of hemoglobin indices after administration of hydroxocobalamin. Smoke-inhalation victims may be exposed to both cyanide and carbon monoxide. Hydroxocobalamin is often empirically administered in the prehospital environment, prior to any diagnostic testing. In these settings, surface oximetry may provide an accurate assessment of hemoglobin indices in patients receiving hydroxocobalamin.
Limitations
This study involved single baseline measurements rather than several measurements over time. This prevented determining device variability independent of hydroxocobalamin. The study was terminated before reaching the a priori sample size due to safety concerns in light of the trial being nontherapeutic. Despite not having robust statistical power, the authors felt the small sample size resulted in minimal impact on co-oximetry readings. The study subjects were all nonexposed volunteers, and it is not clear if the performance of surface oximetry in actual cyanide-exposed victims receiving hydroxocobalamin would be different.
Conclusion
Using the Masimo Radical-7 device, administration of hydroxocobalamin does not significantly impact noninvasive oximetry. Accuracy of measurements in smoke-exposed individuals will require additional study.
Acknowledgements
The opinions and assertions contained herein are the views of the authors and are not to be construed as official or as reflecting the views of the United States Department of Defense. The authors express their gratitude to Dr. Amoroso, Dr. Patten, and the Department of Clinical Investigation (Madigan Army Medical Center, Tacoma, Washington USA) for their support and funding.
