Study design: think 'scientific value' not 'p-values'.

Statistically based experimental designs have been available for over a century. However, many preclinical researchers are completely unaware of these methods, and the success of experiments is usually equated only with 'p < 0.05'. By contrast, a well-thought-out experimental design strategy provides data with evidentiary and scientific value. A value-based strategy requires implementation of statistical design principles coupled with basic project management techniques. This article outlines the three phases of a value-based design strategy: proper framing of the research question, statistically based operationalisation through careful selection and structuring of appropriate inputs, and incorporation of methods that minimise bias and process variation. Appropriate study design increases study validity and the evidentiary strength of the results, reduces animal numbers, and reduces waste from noninformative experiments. Statistically based experimental design is thus a key component of the 'Reduction' pillar of the 3R (Replacement, Reduction, Refinement) principles for ethical animal research.

Use of near-infrared fluorescence angiography with indocyanine green to evaluate direct cutaneous arteries used for canine axial pattern flaps.

OBJECTIVE: To describe the use of near-infrared angiography (NIRFA) to identify the vascularization of three canine axial pattern flaps (APFs) omocervical (OMO), thoracodorsal (THO), and caudal superficial epigastric (CSE); to establish a vascular fluorescence pattern (VFP) grading system; and to evaluate the effect of NIRFA on surgeon flap dimension planning compared to traditional landmark palpation (LP) and visualization assessments. STUDY DESIGN: Experimental study. ANIMALS: A total of 15 healthy, client-owned dogs. METHODS: Dogs were sedated and flap sites were clipped. LP-based margins were drawn and preinjection images were recorded. Indocyanine green (ICG) was administered and VFP images were recorded. VFP scores were determined by five surgeons. Margin alterations were performed based on NIRFA-ICG images. Altered measurements were compared between LP and NIRFA-ICG images. RESULTS: Vascularization of the CSE flap was most visible with NIRFA with VFP scores 4/4 for 13/15 dogs. Intersurgeon agreement for VFP grades was poorest for THO (ICC = 0.35) and intermediate for OMO (ICC = 0.49) flaps. Surgeons were more likely to adjust dimensions for CSE flaps relative to OMO (OR 17.3, 95% CI: 6.2, 47.8) or THO (25.5; 8.6, 75.7). CONCLUSION: Using a grading system, we demonstrated that the CSE flap was most visible. Surgeons were more likely to adjust the LP-CSE flap margins based on fluorescence patterns and were more likely to rely on LP when visualization scores were low. CLINICAL SIGNIFICANCE: NIRFA has possible applications identifying some direct cutaneous arteries of APFs and their associated angiosomes in real-time. Further investigation is indicated to study NIRFA's potential to improve patient specific APF planning.

Lactate to Albumin Ratio Is Not Predictive of Outcome in Septic Dogs: A Retrospective Case-Control Study.

The objective of this study was to investigate the value of the lactate to albumin ratio (L:A) as a prognostic marker for mortality in septic dogs. A single-center retrospective case-control study based on clinical record review was conducted at an academic teaching hospital. All records were extracted for diagnoses of bacterial sepsis, septic peritonitis, septic shock, or septicemia between February 2012 and October 2021. The study included 143 dogs. The most commonly identified sepsis diagnoses in dogs were septic peritonitis (55%; 78/143), unclassified sepsis (20%), and sepsis secondary to wounds or dermatological conditions (10%; 15/143). Median lactate and albumin for all dogs at presentation were 2.80 mmol/L and 2.6 g/dL, respectively; the median L:A ratio was 1.22. No clinically or statistically significant differences in lactate (P = 0.631), albumin (P = 0.695), or L:A (P = 0.908) were found between survivors and nonsurvivors.

Effects of Refined Handling on Reproductive Indices of BALB/cJ and CD-1 IGS Mice.

Current mouse handling methods during cage change procedures can cause stress and potentially compromise animal welfare. Our previous study of breeding C57BL/6J mice found modest increases in pup production and a significant reduction in preweaning litter losses when mice were handled using a tunnel as compared with a tail-lift with padded forceps. The current study evaluated how these 2 handling methods affected reproduction by 2 additional mouse strains, BALB/cJ (a low- to intermediate-fecundity strain) and CD-1 IGS (a high-fecundity stock). We predicted that refined handling would have minimal effects on the high-fecundity line with a satisfactory production rate and greater effects on the low-fecundity line. Handling method (tunnel compared with tail-lift) was randomly assigned to monogamous breeding pairs of mice. Reproductive metrics (litter size at birth and weaning, numbers of litters, litter attrition, between-litter intervals, pup wean- ing weight, and sex ratio) were prospectively monitored for 80 BALB/cJ and 77 CD-1 pairs that were bred continuously for 6 mo. Both strains of mice were highly productive, exceeding previously published breeding data. However, neither strain demonstrated operational or statistically significant differences between handling methods for any reproduction metric. As we detected no negative effects in these 2 strains and the benefits are clear in other strains, refined handling should be considered for all breeding mice.

Geometric, landmark-guided technique reduces tissue trauma, surgery time, and subjective difficulty for canine peripheral lymphadenectomies: an educational crossover study.

OBJECTIVE: To compare the effect of a geometric, landmark-guided lymphadenectomy (LL) approach to peripheral lymph nodes (LNs) on successful LN identification, surgical time, tissue trauma, and ease of LN identification compared to standard lymphadenectomy (SL) and methylene blue-guided lymphadenectomy (MBL). SAMPLE: 18 adult, mixed-breed canine cadavers operated on by 7 veterinarians and 5 fourth-year veterinary students between July 23 and October 12, 2022. METHODS: Participants were provided standardized, publicly available materials regarding the anatomy and surgical techniques for SL of 3 peripheral lymphocentrums: superficial cervical, axillary (ALN), and superficial inguinal (SILN). Participants performed the 3 SLs unilaterally on canine cadavers. Thereafter, they were randomly assigned to 2 crossover groups: MBL and LL. All dissections were separated by at least 2 weeks for each participant. Primary outcome measures included successful LN identification, surgical time, tissue trauma scores, and subjective difficulty. RESULTS: Successful LN identification was highest with LL (86%) compared to SL (69%) and MBL (67%). Subjective difficulty scores were reduced with LL for SILN dissections. Tissue trauma scores were reduced when using LL for ALN and SILN compared to MBL and SL. Time to LN identification was reduced for ALN with LL. No significant differences were observed between MBL and SL, or for the superficial cervical dissections. CLINICAL RELEVANCE: Peripheral lymphadenectomies are time consuming and difficult for veterinarians in early stages of surgical training. Little surgical guidance is provided within current literature. Geometric, landmark-guided lymphadenectomies may improve LN identification success and reduce surgical time, tissue trauma, and procedure difficulty, which could encourage their clinical application.

Superficial anatomic landmarks can be used to triangulate the location of canine peripheral lymphocentrums: superficial cervical, axillary, and superficial inguinal.

OBJECTIVE: To utilize the geometry of superficial anatomic landmarks to guide incisional location and orientation for peripheral lymphadenectomy, document deep anatomic landmarks for lymphocentrum identification, and develop novel surgical approaches to the superficial cervical, axillary, and superficial inguinal lymphocentrums in dogs. ANIMALS: 12 canine cadavers. PROCEDURES: 2 cadavers were used for a pilot investigation to determine optimal body positioning, select superficial anatomic landmarks for lymphocentrum identification, and evaluate novel surgical approaches to the 3 lymphocentrums. These lymphocentrums were then dissected in 10 additional cadavers using these novel surgical approaches. Measurements of the distances from lymphocentrum to landmark and between landmarks were obtained for each lymphocentrum. Deep anatomic landmarks were recorded for each dissection. The mean and SD were calculated for each measurement and used to develop geometric guidelines for estimating the location of each lymphocentrum for these surgical approaches. RESULTS: Each peripheral lymphocentrum was found in the same location relative to the respective, predetermined, superficial, anatomic boundaries in all cadavers. Briefly, the superficial landmarks to each lymphocentrum were as follows: (1) superficial cervical: wing of atlas, acromion process of scapula, greater tubercle of humerus; (2) axillary: caudal border of transverse head of superficial pectoral muscle, caudal triceps muscle, ventral midline; and (3) superficial inguinal: origin of pectineus muscle, ipsilateral inguinal mammary gland, ventral midline. The proposed superficial and deep surgical landmarks were identified within every cadaver. The previously undescribed surgical approaches were effective for lymphocentrum identification. CLINICAL RELEVANCE: Anatomic landmarks provided in this study may help reduce surgical time and tissue trauma during peripheral lymphadenectomy in dogs. This study was also the first to describe a surgical approach to the superficial inguinal lymphocentrum and ventral approaches to the superficial cervical and axillary lymphocentrums and provided previously unpublished anatomic landmarks for a lateral approach to the superficial cervical lymphocentrum.

'Invisible actors'-How poor methodology reporting compromises mouse models of oncology: A cross-sectional survey.

The laboratory mouse is a key player in preclinical oncology research. However, emphasis of techniques reporting at the expense of critical animal-related detail compromises research integrity, animal welfare, and, ultimately, the translation potential of mouse-based oncology models. To evaluate current reporting practices, we performed a cross-sectional survey of 400 preclinical oncology studies using mouse solid-tumour models. Articles published in 2020 were selected from 20 journals that specifically endorsed the ARRIVE (Animal Research: Reporting of In Vivo Experiments) preclinical reporting guidelines. We assessed reporting compliance for 22 items in five domains: ethical oversight assurance, animal signalment, husbandry, welfare, and euthanasia. Data were analysed using hierarchical generalised random-intercept models, clustered on journal. Overall, reporting of animal-related items was poor. Median compliance over all categories was 23%. There was little or no association between extent of reporting compliance and journal or journal impact factor. Age, sex, and source were reported most frequently, but verifiable strain information was reported for <10% of studies. Animal husbandry, housing environment, and welfare items were reported by <5% of studies. Fewer than one in four studies reported analgesia use, humane endpoints, or an identifiable method of euthanasia. Of concern was the poor documentation of ethical oversight information. Fewer than one in four provided verifiable approval information, and almost one in ten reported no information, or information that was demonstrably false. Mice are the "invisible actors" in preclinical oncology research. In spite of widespread endorsement of reporting guidelines, adherence to reporting guidelines on the part of authors is poor and journals fail to enforce guideline reporting standards. In particular, the inadequate reporting of key animal-related items severely restricts the utility and translation potential of mouse models, and results in research waste. Both investigators and journals have the ethical responsibility to ensure animals are not wasted in uninformative research.

Between two stools: preclinical research, reproducibility, and statistical design of experiments.

Translation of animal-based preclinical research is hampered by poor validity and reproducibility issues. Unfortunately, preclinical research has 'fallen between the stools' of competing study design traditions. Preclinical studies are often characterised by small sample sizes, large variability, and 'problem' data. Although Fisher-type designs with randomisation and blocking are appropriate and have been vigorously promoted, structured statistically-based designs are almost unknown. Traditional analysis methods are commonly misapplied, and basic terminology and principles of inference testing misinterpreted. Problems are compounded by the lack of adequate statistical training for researchers, and failure of statistical educators to account for the unique demands of preclinical research. The solution is a return to the basics: statistical education tailored to non-statistician investigators, with clear communication of statistical concepts, and curricula that address design and data issues specific to preclinical research. Statistics curricula should focus on statistics as process: data sampling and study design before analysis and inference. Properly-designed and analysed experiments are a matter of ethics as much as procedure. Shifting the focus of statistical education from rote hypothesis testing to sound methodology will reduce the numbers of animals wasted in noninformative experiments and increase overall scientific quality and value of published research.

Effects of non-aversive versus tail-lift handling on breeding productivity in a C57BL/6J mouse colony.

Non-aversive handling is a well-documented refinement measure for improving rodent welfare. Because maternal stress is related to reduced productivity, we hypothesized that welfare benefits associated with non-aversive handling would translate to higher production and fewer litters lost in a laboratory mouse breeding colony. We performed a randomized controlled trial to examine the effects of a standard method of handling (tail-lift with forceps) versus non-aversive handling with transfer tunnels ('tunnel-handled') on breeding performance in 59 C57BL/6J mouse pairs. Intervention assignments could not be concealed from technicians, but were concealed from assessors and data analyst. An operationally significant effect of tunnel-handling (large enough differences to warrant programmatic change) was defined before study initiation as a 5% increase in productivity, or one extra pup over the reproductive lifetime of each pair. Pairs were randomly allocated to handling intervention and cage rack location, and monitored over an entire 6-month breeding cycle. For each group, we measured number of pups born and weaned, and number of entire litters lost prior to weaning. Differences between transfer methods were estimated by two-level hierarchical mixed models adjusted for parental effects and parity. Compared to tail-lift mice, tunnel-handled mice averaged one extra pup per pair born (+1.0; 95% CI 0.9, 1.1; P = 0.41) and weaned (+1.1, 95% CI 0.9, 1.2; P = 0.33). More tunnel-handled pairs successfully weaned all litters produced (13/29 pairs, 45% vs 4/30 pairs, 13%; P = 0.015), averaged fewer litter losses prior to weaning (11/29 pairs [38%] vs 26/30 pairs [87%]; P <0.001), and had a 20% lower risk of recurrent litter loss. The increase in numbers of pups produced and weaned with tunnel handling met threshold requirement for operational significance. These data and projected cost savings persuaded management to incorporate tunnel handling as standard of care across the institution. These data also suggest that overlooked husbandry practices such as cage transfer may be major confounders in studies of mouse models.

Right axis deviation in the canine electrocardiogram for predicting severity of pulmonic stenosis: a retrospective cohort analysis.

OBJECTIVE: To investigate the predictive value of right axis deviation of the mean electrical axis (MEA) in assessing the severity of pulmonic stenosis (PS) in dogs. ANIMALS: Records for 218 client-owned dogs diagnosed between 2014 and 2020 with PS as determined by Doppler echocardiography. PROCEDURES: University of Florida Small Animal Clinic medical records were reviewed, and signalment and clinical risk variables (murmur grade and clinical signs) were extracted. MEA was determined from ECG records by use of leads I and III. Predictive potential of MEA and associated risk factors to diagnose PS severity (mild [< 50 mm Hg], moderate, or severe [> 75 mm Hg]) were assessed by receiver-operating characteristic curve analysis and quantile regression. RESULTS: Records for 88 dogs were eligible for analysis. Greater PS severity was associated with smaller breeds presenting with ECG abnormalities, overt clinical signs, and high-category murmur grades (IV and V). Mean MEA increased with stenosis severity category, with an average of 62° for mild, 113° for moderate, and 157° for severe. Each 10° increase in MEA corresponded to an approximately 5-mm Hg increase in PG. Increasing PS severity was associated with MEA right axis deviation > 100° and the more severe cases (PG > 75 mm Hg) with MEA right axis deviation > -180°. CLINICAL RELEVANCE: Mean electrical axis right axis deviation may be a useful screening metric for dogs with suspected moderate to severe PS.

Evaluation of clinical examination location on stress in cats: a randomized crossover trial.

OBJECTIVES: The objective of this study was to quantify the effects of owner separation and physical examination location on fear, anxiety and stress (FAS) behavioral indicators in cats. METHODS: The study was a prospective, non-blinded, randomized, two-period, two-treatment crossover trial. Healthy adult cats presenting for wellness or dental evaluations at a single veterinary teaching hospital received three physical examinations: a baseline assessment (owner present) followed by physical examinations in both a treatment area (owner absent [TAOA]) and an examination room (owner present [EROP]). The physical examination sequence order was randomized. Low-stress handling techniques were used for all examinations. The primary endpoints were heart rate (HR; beats per min [bpm]) and total FAS scores. HR was measured by auscultation, and FAS by five specific behaviors scored as 0/1 and summed for each assessment period. RESULTS: Twenty-one healthy cats were enrolled. HR measured at entry (baseline) was a significant determinant of subsequent HR readings. HR measured during examinations conducted in both EROP and TAOA were elevated to levels indicative of stress (>180 bpm). HR was significantly higher for TAOA relative to EROP (30 bpm, 95% confidence interval 18-43; P <0.001). Behavioral FAS scores showed no statistically significant effects of sequence or room. FAS scores for TAOA assessments were clinically elevated relative to baseline (1.5 FAS, SE 0.7; P = 0.05); EROP FAS scores relative to baseline did not differ statistically (0.5 units, SE = 0.5; P = 0.43). CONCLUSIONS AND RELEVANCE: Owner separation coupled with physical examination location can result in clinically significant increases in perceived stress in cats, and compromise vital sign assessments. Whenever possible, physical examinations and procedures should take place with the owner present with separation from unfamiliar dogs and cats.

Preclinical Research Reporting in Shock: Room for Improvement.

ABSTRACT: The ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines were endorsed by the Shock Society in 2012, but to date there has been no systematic evaluation of research reporting quality for Shock. We systematically assessed 100 randomly selected animal-based research articles published between 2014 and 2018 for reporting quality and statistical practice, compared with 40 pre-ARRIVE studies. More than half of surveyed papers omitted verifiable ethical oversight information and basic animal descriptive information. Few papers reported best-practice methods, such as sample size justification (10%), randomization (43%), randomization method (7%), blinding (23%). Only one paper reported effect sizes to interpret study results. Most troubling was inadequate reporting of welfare-related information (anesthesia, analgesia, humane endpoints, euthanasia). Almost a decade after ARRIVE endorsement, our findings show that reporting deficiencies have persisted with little sign of correction. There is a clear need for investigators to increase transparency of research methods reporting, and drastically improve skills in experimental design. Improvement in standards and greater attention paid to reporting will lead to improvement in reproducibility, replicability, and research quality. It is incumbent upon the research community to improve reporting practices; accurate and transparent reporting is integral to producing rigorous and ethical science.

When Evidence Goes "Missing in Action": Implications for Patient Management in Cardiac Surgery.

Best-practice clinical decision-making for patient blood management (PBM) and transfusion in cardiac surgery requires high-quality, timely information. However, evidence will be misleading if published information lags too far behind evolving practice, or if trial results are biased, incomplete, or unreported. The result is that providers are deprived of accurate data, and patients will not receive best possible care. Publicly accessible trial registries provide information for structured audits of reporting compliance, and appraisal of evidence attrition and distortion. Trials related to blood management and transfusion in cardiac surgery and those registered in ClinicalTrials.gov were evaluated for relevance, reliability, transparency, timeliness, and prevalence of unreported trial results. Evidence was considered to have "disappeared" if no results were posted to the registry and no related PUBMED publications were available by July 2019. Data were summarized by descriptive statistics. A total of 181 registered trials were surveyed; 52% were prospectively registered. Most commonly reported primary outcomes were laboratory surrogate measures (34%). Patient- and practice-relevant outcomes-mortality/major morbidity (7%), transfusion (27%), and major bleeding (28%)-were less common. Only seven studies posted results to the registry within the mandated 12 months from study completion; median time to posting was 17 (interquartile range [IQR] 13, 37) months. Trial results for 58% were unreported 3-9 years after trial completion. A staggering amount of clinical trial evidence for PBM in cardiac surgery is missing from publicly accessible records and the literature. Investigators must be incentivized to promptly and completely report all results. Penalties for noncompliance are already in place and should be enforced. Simplified information linkage, centralized and routine audit cycles, and prioritization of robust "living" reviews may be more positive motivators. Implementation will require a sea change in the prevailing culture of research reporting, plus coordinated efforts of clinicians, applied statisticians, information technology specialists, and research librarians.

Gap Analysis of Swine-Based Hemostasis Research: "Houses of Brick or Mansions of Straw?"

INTRODUCTION: Hemorrhage control is the top priority in far-forward care. Preclinical studies are essential for determining safety and efficacy before novel therapeutics can be tested in humans. Unfortunately, poor methodological quality jeopardizes translational potential. METHODS: We systematically reviewed 136 recent publications describing swine models of hemostasis and hemorrhage reduction to assess compliance with established standards for scientific reporting. Quality measures were summarized by descriptive statistics; randomization was assessed by using baseline group differences to test the uniform distribution assumption for observed P-values. RESULTS: Most articles did not report information essential to assess study validity and reliability of experimental results. Studies claiming random allocation showed clear evidence of systematic bias. Sample sizes were small, but nearly all studies reported statistically significant effects in the direction of "benefit." Excessive hypothesis testing increased the risk of false positives. CONCLUSIONS: Methodological quality was poor. Although funding agencies actively promote good scientific practice, investigators have been slow to comply. Poorly executed and reported animal research is an ethical and translational issue, wasting animals and potentially harming patients. To properly assess the therapeutic benefit of novel interventions, investigators must rely less on rote hypothesis testing, develop skills in experimental design and quantitative analysis, and comply with best-practice reporting guidelines.

Improving Reproducibility and Transparency in Shock: the Arrive Guidelines Need Better Implementation and Enforcement.

Reporting standards for animal research in Shock have not improved since Shock Society endorsed the ARRIVE guidelines in 2012. Particularly troubling is the omission of key information describing methodological quality and animal welfare. Both investigators and journal reviewers are strongly encouraged to actively consult the checklist to improve manuscript quality, and ensure that Shock upholds the highest standards of research quality and the humane treatment of animals.

Temporal map of the pig polytrauma plasma proteome with fluid resuscitation and intravenous vitamin C treatment.

BACKGROUND: Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems. OBJECTIVES: We applied quantitative mass spectrometry-based proteomics [liquid chromatography-mass spectrometry (LC-MS/MS)] to map the effects of fluid resuscitation and intravenous vitamin C (VitC) in a pig model of polytrauma (hemorrhagic shock, tissue injury, liver reperfusion, hypothermia, and comminuted bone fracture). The goal was to determine the effects of VitC on plasma protein expression, with respect to changes associated with coagulation and trauma-induced coagulopathy (TIC). METHODS: Longitudinal blood samples were drawn from nine male Sinclair pigs at baseline, 2 h post trauma, and 0.25, 2, and 4 h post fluid resuscitation with 500 mL hydroxyethyl starch. Pigs were treated intravenously (N = 3/treatment group) with saline, 50 mg VitC/kg (Lo-VitC), or 200 mg VitC/kg (Hi-VitC) during fluid resuscitation. RESULTS: A total of 436 plasma proteins were quantified of which 136 changed following trauma and resuscitation; 34 were associated with coagulation, complement cascade, and glycolysis. Unexpectedly, Lo-VitC and Hi-VitC treatments stabilized ADAMTS13 levels by ~4-fold (P = .056) relative to saline and enhanced ADAMTS13/von Willebrand factor (VWF) cleavage efficiency based on LC-MS/MS evidence for the semitryptic VWF cleavage product (VWF1275-1286 ). CONCLUSIONS: This study provides the first comprehensive map of trauma-induced changes to the plasma proteome, especially with respect to proteins driving the development of TIC.

Informing efficient pilot development of animal trauma models through quality improvement strategies.

Poor quality data in preclinical trials can result from inconsistent and unstandardized experimental processes. Unpredictable pre-intervention variability generates unreliable data, biases outcomes and results in needless waste of animals and resources. We applied Define-Measure-Analyse-Improve-Control (DMAIC) quality improvement processes to pilot development of a swine model of trauma, haemorrhagic shock and coagulopathy. The goal was to reduce variability through protocol standardization and error reduction. Six male Sinclair swine were sequentially anesthetized, intubated, mechanically ventilated and instrumented, then subjected to multiple-hit injury, followed by fluid resuscitation monitoring and coagulation testing. Experimental tasks were defined and mapped. Performance measures were task performance times, subject stabilization time and number of task execution errors. Process improvement was assessed by reduced times and errors, and subject stability at target physiological values. Previously-overlooked performance errors and deficiencies were identified. 'Mistake-proofing' actions included personnel retraining, revisions of standard operating procedures and use of checklists. The quality improvement pilot trial produced a stable model with reduced protocol deviations. Data quality can be improved and animal waste minimized, if experimental planning incorporates strategies to ensure protocol adherence and reduced operator performance variation and errors. Properly designed pilot trials can be essential components of refinement and reduction strategies in animal-based research.

Old Tricks for New Dogs? John Caddy and the Victorian Origins of TCCC.

The success of Tactical Combat Casualty Care (TCCC) in reducing potentially preventable combat deaths may rely on both specific interventions (such as tourniquets) and the systematized application of immediate care. Essential elements of a combat care system include clear specification of immediate care priorities, standardized methodology, and inclusion and training of all nonmedical personnel in early response. Although TCCC is fairly recent, the construct is similar to that first suggested during the mid-nineteenth century by John Turner Caddy (1822-1902), a British Royal Navy staff surgeon. Although naval warfare engagements at the time were relatively infrequent, casualties could be numerous and severe and often overwhelmed the small medical staff on board. Caddy recognized that nonmedical personnel properly trained in the fundamentals of combat injury management would result in lives saved and greatly improved morale. The novelty was in his attempt to make procedures simple enough to be performed by nonmedical personnel under stress. However, Caddy's guidelines were completely overlooked for nearly two centuries. The principles of best practice for managing combat trauma injuries learned in previous wars have often been lost between conflicts. Understanding the historical roots of combat first responder care may enable us to better understand and overcome barriers to recognition and retention of essential knowledge.