REFEREED

Evidence-Based Treatment for Laminitis—What Works?Rustin M. Moore, DVM, PhD, DACVS

CLINICAL TECHNIQUES

ABSTRACT

Acute or recurrent laminitis often results in markedstructural or mechanical disruption of the hoof with ro-tation or sinkage of the coffin bone within the hoofcapsule in affected horses or those predisposed to devel-oping this complex and devastating disease. A completeknowledge and understanding of laminitis and its com-plex pathophysiologic cascade remains elusive despitethe substantial time and effort that many scientists andclinicians have dedicated over the last few decades. Asa result, preventive and therapeutic management strate-gies remain empirical and anecdotal, with little emphasison evidence-based medicine. Evidence-based medicineinvolves integrating individual clinical expertise with ex-ternal clinical evidence from systematic research to makethe best possible decisions regarding patient manage-ment. Numerous and overlapping theories have beenpostulated for the pathophysiology of laminitis. Al-though beyond the scope of this discussion, the currentmost commonly discussed theories include vascular orischemic, inflammatory, metabolic, enzymatic, and bio-mechanical. In reality, many of these pathways or othersyet to be identified are likely involved in the complex cas-cade of acute laminitis. Substantial focused and relevantresearch is needed to advance our knowledge and under-standing of this complex disease and to develop more ef-fective preventive and therapeutic strategies based onsound scientific and clinical evidence.

INTRODUCTIONAcute laminitis is a severely debilitating, excruciatingly pain-ful, and potentially career-ending and life-threatening dis-ease of the sensitive and insensitive laminae of the equinedigit. Laminitis is important to all horse owners/trainersand horse enthusiasts because it can occur in adult horsesand ponies of any breed or use. Laminitis usually occurs sec-ondary to other diseases such as acute gastrointestinal tractdisease, particularly strangulatingobstructionand inflamma-tory bowel disease; grain overload; retained fetal membranesand subsequent metritis; pleuropneumonia; and other

From the Department of Veterinary Clinical Science, College of Veterinary Medicine,

The Ohio State University, Columbus, OH.

Reprint requests: Rustin M. Moore, DVM, PhD, DACVS, From the Department of

Veterinary Clinical Science, College of Veterinary Medicine, The Ohio State

University, Columbus, OH.

0737-0806/$ - see front matter

� 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.jevs.2008.01.015

176

diseases accompanied by endotoxemia. Additionally, sup-porting limb laminitis occurs commonly in the contralaterallimb because of overload or excessive weight bearing inhorses that have a severe non�weight-bearing lameness.

Complete knowledge and understanding of laminitis andits complex pathophysiologic cascade remain elusive de-spite substantial efforts by many scientists and cliniciansover the last few decades. Thus preventive and therapeuticmanagement strategies remain empirical and anecdotalwith little emphasis on evidence-based medicine. Numer-ous and overlapping pathophysiologic theories have beenpostulated. Although beyond the scope of this discussion,the current most commonly discussed pathophysiologictheories include: (1) vascular or ischemic; (2) inflamma-tory; (3) metabolic; (4) enzymatic and (5) biomechanical.

Evidence-based medicine involves integration of individ-ual and collective clinical experience and expertise withscientific evidence from sound biomedical research tomake the best decisions regarding strategies for managingand treating patients.1 Progress in the treatment and pre-vention of laminitis must be made using evidence gainedthrough a combination of (1) well-designed observationaland epidemiologic studies of naturally acquired spontane-ous laminitis; (2) well-documented experiences of clini-cians and farriers working cohesively in caring for horseswith laminitis based on objective criteria; (3) blinded andcontrolled clinical trials involving horses with naturally ac-quired laminitis; and (4) well-designed, scientifically soundstudies using in vitro cell culture techniques, experimen-tally induced models of laminitis, and leading-edge molec-ular and cellular approaches.

This report is designed to provide some recent examplesin which research provides some insight and evidence forthe use or disuse of certain preventive and therapeutic mo-dalities for horses with lamintis or those predisposed todeveloping it. Substantial focused research is needed toadvance our knowledge and understanding of this complexdisease and to develop more effective preventive and ther-apeutic strategies that are based on sound scientific andclinical investigations. The following are selected examplesof evidence supporting or refuting effectiveness of variouspreventive or therapeutic modalities:

DISTAL LIMB CRYOTHERAPYPollitt and van Epps2 demonstrated prolonged continuousdistal limb cryotherapy consistently maintained a decrease inhoof wall temperature of approximately 2.88C throughouta 48-hour period and seemed to be well tolerated with no

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adverse signs observed, including no development of lame-ness and no visible hoof abnormalities. Applying an iceslurry to the level of the fetlock effectively cools the hoof.Worster et al3 showed (via scintigraphy) that cryotherapydecreased soft tissue perfusion of the digit for 30 minutes.Unlike in other animals, it appears that reflex intermittentvasodilation does not occur in horses. One explanation isthat this phenomenon, which is believed to be largely attrib-utable to dilation of blood vessels in muscle tissue, does notoccur in the distal limb of horses because of an absence ofmuscle tissue in the equine distal limb. Work in humansand laboratory animals suggests that, to be maximally effec-tive, cryotherapy needs to consistently and continuouslydecrease tissue temperature to less than 58C.

Distal limb cryotherapy started before and applied contin-uously for 48 hours after oligofructose administration mark-edly reduced the severity of experimentally induced laminitisin horses.4 In this study by van Epps and Pollitt,4 the hoofwall temperature was maintained at less than 58C through-out the period and seemed well tolerated. The cryotherapycompletely prevented histopathologic evidence of laminitisin two of six treated horses, and the remaining four onlyhad mild histopathologic changes, including slight elonga-tion of secondary epidermal lamellae or changes in basalcell nuclear morphology andposition. The key lesion of lam-initis reported by the investigators in the untreated feet ofoligofructose-treated animals, the detachment of the base-ment membrane from the secondary epidermal lamellae,was not observed in limbs treated with cryotherapy. Thisalso seemed to correlate subjectively with the absence of ex-pected lameness in the treated limb. Hoof wall temperatureremained consistently low throughout the application pe-riod, which suggests that the sublamellar perfusion andmetabolic rate remained consistently low.

Vascular and hypometabolic effects of cryotherapy providesome insight into thepathophysiology of laminitis.Thevaso-constrictive effects are postulated to be beneficial by decreas-ing the delivery of ‘‘laminitis trigger factors’’ to the digitalcirculation. The hypometabolic effect appears more complexbut also is likely to be the cause of any benefit from cryother-apy. Cryotherapy directly or indirectly reduced lamellar ex-pression of MMP-2 in horses administered oligofructoseand prevented development of significant histopathologic la-mellar changes. Although not studied, it is possible that cryo-therapy reduced or prevented inflammatory cell infiltration.In summary, the authors present evidence to suggest a bene-ficial effect of applying continuous cryotherapy for an ex-tended period in horses at risk of developing laminitis.

INTRAMUSCULARLY ADMINISTEREDACEPROMAZINEIn an attempt to alter vascular events associated with the de-velopment of laminitis, veterinary practitioners often employ

various treatments and preventive measures to help normal-ize digital blood flow and perfusion during acute stages oflaminitis. Slater et al reported that acepromazine was usedin 57% of acute laminitis cases for prevention or treatmentof laminitis in one study.5 In a survey of 60 scientists and cli-nicians, more than 93% reported that they use acepromazineroutinely (58%) or occasionally (35%) for prevention andtreatment of acute laminitis.6 Acepromazine inhibits alpha-adrenergic receptors, causing peripheral vasodilation, whichresults in systemic hypotension. Ingle-Ferr et al7 and Huntet al8 both reported significant increases in palmar digital ar-terial blood flow in healthy conscious horses 50 to 75 min-utes after an intravenous injection (0.02 and 0.04 mg/kgbody weight) of acepromazine. Palmar digital veins of horseshave a greater in vitro vasodilatory response to acepromazinecompared withpalmardigital arteries, suggesting that the in-crease in digital blood flow could be attributed to decreasedperipheral vascular resistance resulting from alpha-adrener-gic receptor blockade.

Leise et al9 recently completed a study in which theyassessed the effects of intramuscularly administered acepro-mazine (0.04 mg/kg) on digital hemodynamics in clini-cally healthy conscious horses. An ultrasonic Dopplerflow probe was surgically implanted around the medial pal-mar digital artery 5 to 7 days before the study in 12 horses.On the day of the study, catheters were placed in the trans-verse facial artery, lateral palmar digital artery, and jugularvein. Horses were divided into two groups. A treatmentgroup (n ¼ 6) received 0.04 mg/kg body weight of ace-promazine intramuscularly. A control group (n ¼ 6) re-ceived an equivalent volume of saline intramuscularly.Palmar digital blood flow and palmar digital and transversefacial arterial pressures were measured at selected times 30minutes before injection and for 6 hours after administra-tion. Jugular venous blood was collected for measurementof packed cell volume and total plasma protein concentra-tion. Heart rate, respiratory rate, and rectal temperaturewere also monitored throughout the study.

A significant increase in palmar digital arterial blood flowwas noted over time when compared with the respectivebaseline value in the acepromazine-treated group. How-ever, this increase in palmar digital arterial blood flow wasnot significantly different between the treated and controlgroups of horses. The increase in digital blood flowobserved in the acepromazine-treated group was similarto reports with intravenous administration at doses rangingfrom 0.02 to 0.066 mg/kg of body weight. An increaseddiameter of the metatarsal artery and the volumetric flowrate also has been reported in horses after intravenousadministration of acepromazine dosed at 0.055 mg/kg ofbody weight.10 The increase in digital blood flow reportedin this study is most likely associated with acepromazine’sblockade of alpha-adrenergic receptors and the subsequent

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decrease in peripheral vascular resistance resulting in anincrease in digital blood flow.

Acepromazine administered intramuscularly decreasessystemic arterial pressure, increases digital blood flow,and decreases packed cell volume when compared with re-spective pretreatment baseline values. Intramuscular ad-ministration of acepromazine has a prolonged effect onsystemic and digital hemodynamic variables in healthy con-scious horses with minimal sedation. Further evaluation ofthese variables is needed in horses during the developmen-tal phase of acute laminitis and in horses at risk of develop-ing laminitis to determine whether similar effects occur.

The effects on palmar digital arterial blood flow may havebeen of greater magnitude if a higher dosage of aceproma-zine had been used. However, a higher dosage may be con-traindicated, because the dose used in the current studysignificantly reduced facial arterial blood pressure toa mean low of 78 mmHg. Further reduction in blood pres-surecould impair tissueperfusion,particularly in systemicallycompromised horses. Additionally, the effects of intramus-cular acepromazine may affect the digital vasculature differ-ently in horses during the developmental phase of acutelaminitis. Further research in these areas may be warranted.

TOPICALLY APPLIED NITROGLYCERINETopical application of nitroglycerine ointment becamea common treatment in laminitis cases after a report inwhich lameness in ponies with pasture-associated laminitisappeared to improve with nitroglycerine administration.11

However, more in-depth physiologic studies (discussedlater) have not confirmed any efficacy of topical nitroglyc-erine in improving digital blood flow. In one study, digitalblood flow was measured via an ultrasonic Doppler flowprobe surgically implanted around the medial palmar digi-tal artery in eight clinically healthy horses.12 Blood was col-lected from a catheter placed in the medial palmar digitalvein for quantification of NO. Nitroglycerine (NTG)patches, NTG ointment, or control patches were placedover the palmar digital vessels at the level of the fetlock.Two horses received an intra-arterial infusion of a NTG so-lution into the medial palmar digital artery in a pilot study.

Digital arterial blood flow did not change significantlywith application of NTG patches, NTG ointment, orcontrol patches. There were no statistically significant orbiologically important changes in digital venous NO con-centrations across time or between treated and controlhorses. In the pilot study, digital arterial blood flow andpalmar digital venous NO concentrations increased withintra-arterial infusion of NTG.

In clinically healthy horses, digital arterial blood flow anddigital venous plasma nitric oxide concentrations did notchange significantly with topically applied NTG. Thesetreatments are unlikely to have an effect on the digital

vasculature of laminitic horses; however, further investiga-tion is warranted. Although NTG patches have been usedas a method of decreasing vasomotor tone and improvingdigital blood flow in horses with laminitis, this study pro-vides evidence in healthy conscious horses that this treat-ment is not effective in altering digital blood flow.

ROLE OF INFLAMMATION ANDCYCLOOXYGENASE ACTIVATIONAnti-inflammatory therapy has remained a central compo-nent of laminitis pharmacotherapy over the years. Belknapet al13,14,15 and others have reported that in the develop-mental stage of laminitis (a time when the animal is exhibit-ing no signs of lameness hoof warmth, pulses, and so forth)there is an intense inflammatory process occurring in thedigital laminae as evidenced by influx of leukocytes, andfrom 5-fold to 400-fold increases in laminar expression ofinflammatory mediators such as cytokines and cyclooxyge-nase-2 (COX-2). Blikslager et al13 reported expression ofCOX-2 by most viable epithelial cells in both laminae andskin. COX-1 exhibited similar epithelial expression toCOX-2 in skin epidermis but was expressed exclusively inthe basal layer of laminar epidermis. COX-1 protein wasnot detectable in dermal vasculature of equine skin or lami-nae, whereas COX-2 was present in endothelial and vascularsmooth muscle cells of dermal vasculature in both skin andlaminae in horses in developmental (early) and acute (later)stages of laminitis induced by black walnut extract (BWE)and in control horses at corresponding times. A marked in-crease in laminar COX-2 protein concentrations was de-tected on immunoblotting in horses in the developmentaland acute stages; however, a lesser increase was observedin horses in the acute stages. Therefore, it appears thatCOX-2 protein expression is markedly increased in the res-ident laminar cell types in the developmental stage of BWE-induced laminitis.

Although some of these inflammatory mediators appearto peak in the prodromal phase (ie, COX-2), this inflamma-tory process continues into the acute stage of the disease,when horses begin to exhibit signs of digital pain. There-fore, aggressive, prudent use of nonsteroidal anti-inflam-matory drugs (NSAIDs) is probably indicated in the horseknown to be at risk for laminitis (eg, colitis, grain overload)until approximately 48 to 72 hours after the animal lastshows clinical signs of toxemia. In addition to blockingthe COX enzymes, high doses of NSAIDs recently havebeen found to block other inflammatory pathways, includ-ing some controlling basic inflammatory gene expression,now known to be occurring in the early stages of laminitis.C0X-2 has recently been shown to be an important media-tor in the synapses of sensory neurons; therefore, COX-2inhibition is likely not only to decrease laminar inflamma-tion, but to decrease central pain sensation. Because of

RM Moore � Vol 28, No 3 (2008) 179

the gastrointestinal and renal toxicity caused by NSAIDs,close attention needs to be paid to the animal’s history, hy-dration status, and clinicopathologic data.

Lidocaine and dimethyl sulfoxide are other medicationswith anti-inflammatory properties. There have been noconclusive studies to demonstrate effectiveness or lackthereof in horses with or predisposed to developing lamini-tis. Currently, a study is ongoing that examines effects of li-docaine in preventing the inflammatory response andleukocyte extravasation associated with laminitis experi-mentally induced with administration of black walnut ex-tract. There have been contradictory findings regardingthe anti-inflammatory and vascular/blood flow effects ofpentoxifylline in horses; however, it has not yet been evalu-ated in horses with laminitis.

INSULIN RESISTANCE AND LAMINITISInsulin is a major regulatory hormone in glucose and fatmetabolism, vascular function, inflammation, tissue re-modeling, and the somatotropic axis of growth. Insulin re-sistance alters insulin signaling by decreasing insulin actionin certain resistant pathways while increasing insulin signal-ing in other unaffected pathways via compensatory hyperin-sulinemia. In humans, altered insulin signaling is implicatedin reduced glucose availability to insulin-sensitive cells, va-soconstriction and endothelial damage, and inflammatoryresponse. Although no direct evidence exists for insulin’srole in these mechanisms in the laminitic horse, changesin glucose availability, vasculature, and inflammation wereall demonstrated in hoof separation.16,17 Insulin resistancewas first implicated in the pathogenesis of laminitis in the1980s, using tolerance tests. Work by Treiber et al18 pro-vides evidence of insulin resistance as a predisposing condi-tion for laminitis. Specific quantitative tests that distinguishinsulin resistance are essential to identify ponies/horses inneed of special management to avoid laminitis. Potentialmanagement strategies to avoid laminitis by increasing in-sulin sensitivity include reducing obesity, increasing exer-cise, and moderating dietary carbohydrates (particularlystarch).

TAKE HOME MESSAGEFocused and relevant research is needed to advance ourknowledge and understanding of laminitis and to developmore effective preventive and therapeutic strategies basedon sound scientific and clinical evidence. It is essential thatpreventive and treatment strategies are evaluated in a scien-tific manner to develop clear evidence regarding the efficacyor lack of effectiveness of such modalities. Additionally, it isimportant to recognize horses predisposed to develop lam-initis and to initiate preventive and therapeutic strategiesearly to maximize the chances of success.

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