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The Potential of Osteopathic Manipulative Treatment in Antimicrobial Stewardship: A Narrative Review Donald R. Noll, DO

Financial Disclosures: The contemporary management of infectious diseases is built around anti­ None reported. microbial therapy. However, the development of antimicrobial resistance Support: None reported. threatens to create a post–antibiotic era. Antimicrobial stewardship at­ Address correspondence to tempts to reduce the development of antimicrobial resistance by improving Donald R. Noll, DO, their appropriate use. Osteopathic manipulative treatment as an adjunctive Professor of Medicine, Department of Geriatrics treatment has the potential for enhancing antimicrobial stewardship by en­ and Gerontology, hancing the human immune system, shortening the duration of antimicro­ New Jersey Institute bial therapy, reducing complications, and improving treatment outcomes. for Successful Aging, Rowan University School The present article reviews the evidence published in the literature since this of Osteopathic Medicine, unique treatment approach was first developed more than 100 years ago. 42 E Laurel Rd, Suite 1800, Stratford, NJ 08084-1338. The evidence suggests that adjunctive osteopathic manipulative treatment has great potential for enhancing antimicrobial stewardship and should be E-mail: [email protected] further investigated. Submitted J Am Osteopath Assoc. 2016;116(9):600-608 January 27, 2016; doi:10.7556/jaoa.2016.119 revision received March 13, 2016; accepted April 13, 2016. here are 2 strategies for treating patients with infectious disease. The first is to target the organism with an appropriate antimicrobial agent. In 1907, Paul Ehrlich developed his “magic bullet” arsphenamine (Salvarsan) and thus began the mod- T 1 ern antibiotic era. Since then the number of safe and effective antimicrobials has greatly increased1 so that today the treatment of patients with infectious disease is built around the use of antimicrobials.2 The second strategy is to support and enhance the human immune system so that the body will heal itself. Supportive care interventions fall into the latter category as they stabilize the patient long enough for the human immune system to mount an effective defense. Examples of supportive care interventions include administration of intravenous fluids, management of comorbidities, surgical drainage of abscesses, vaccina- tion, nutritional support, incentive spirometry, chest physiotherapy, and early mobilization. Antimicrobial therapy is so central to contemporary management of infectious diseases that all other interventions are considered to be adjunctive and have been given relatively little attention. Concerns are growing about antimicrobial resistance and are triggering calls for in- creased antimicrobial stewardship.2-4 The World Health Organization report on global anti- microbial resistance states that a post–antibiotic era—in which common infections and minor injuries can kill—is far from being an apocalyptic fantasy but is instead a very real possibility for the 21st century.5 Antimicrobial stewardship seeks to optimize the appropriate use of antibiotics with the goal of minimizing the development of antimicrobial resistance.3,6 Antimicrobial stewardship programs are formal efforts to avoid the overuse and misuse of

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antibiotics.7 Strategies for enhancing antimicrobial stew- tained by collecting serum leukocytes and measuring ardship include surveillance for antimicrobial resistance; the average number of bacilli ingested by 100 leuko- improved use through education, clinical practice guide- cytes. His study design was a simple collection of lines, and policy; communication training; and enhanced baseline blood samples, mechanical stimulation of the laboratory testing, including the use of biomarkers to liver and spleen, and then collection of posttreatment confirm infection.3,6 One intervention not discussed in blood samples at various times after treatment.17 A these systematic reviews3,6 that has the potential to en- contemporary statistical analysis of his raw data hance antimicrobial stewardship is osteopathic manipula- (Table) suggests that liver and splenic stimulation does tive treatment (OMT). increase the phagocytic index over baseline for the first When OMT was first developed more than 100 years 2 hours after treatment. In the 1930s, Yale Castlio, DO, ago, infectious diseases were the dominant cause of mor- and Louise Ferris-Swift, DO, studied the effect of the bidity and mortality.4 It was the death of his 3 children splenic pump technique on individuals hospitalized for from an infectious disease that was a major impetus for various infectious diseases.18 They collected baseline , MD, DO, to develop OMT.8 In his blood samples on 100 individuals, applied the splenic autobiography, Still attributed the deaths to spinal men- pump technique, and then drew 2 posttreatment blood ingitis but later blamed the deaths of his 3 children on a samples at 7 different time intervals, allowing for contaminated water supply.8,9 Many OMT techniques paired comparisons of 25 or 50 individuals. A contem- were created specifically to treat patients with infections, porary analysis19 of their raw data showed that the regardless of the cause.10 Early osteopathic physicians splenic pump modestly increased serum white blood (ie, DOs) dreamed of defeating all infectious diseases by cell counts, reduced red blood cell counts, decreased enhancing the human immune system using OMT.11,12 In the Arnath index, and increased serum reticulocyte an essay discussing pneumonia, Still outlined his under- counts. The most robust changes from baseline were pinning philosophy that health is the result of a perfectly the immune function tests. Splenic pumping signifi- adjusted body and that disease is caused by the failure of cantly improved the mean phagocytic index, the op- the “osteopathic engineer” to obtain the normal position sonic index, the serum agglutinative power, and the of every bone, muscle, and nerve.13 The classic osteo- serum bacteriolytic power after treatment.19 pathic view is that OMT added to antimicrobial therapy In the 1920s, C.E. Miller, DO, developed the lym- will improve the chances of recovery from any infec- phatic pump technique for the express purpose of tion.14,15 Contemporary DOs still believe in OMT’s po- treating patients with all types of infectious diseases. tential role in managing infectious diseases, such as in His idea was that enhancing the lymphatic absorption the event of a serious influenza pandemic.16 This article of toxins (antigens) to the lymphoid tissues would en- reviews the evidence for using OMT as an adjunctive hance the production of antitoxins (antibodies) to fight treatment to antimicrobial therapy and its potential role infection.20 He originally attempted to do this by in antimicrobial stewardship. having the patient lie supine on the treatment table. Standing above the head with the 4 fingers of his hand in the axilla and the thumb just below the clavicle, Mechanistic Evidence Miller would gently pull or milk the lymphatic In 1912, C.A. Whiting, ScD, DO, studied the effects of glands.20 By 1927, his technique had evolved by liver and splenic stimulation on immune function using moving the operator’s hands medially to rest just under rhythmic compressions.17 A phagocytic index was ob- the clavicles over the terminal points of the thoracic

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Table. Contemporary Analysis of Whiting’s 1912 Measurements17 of the Phagocytic Index in 2 Patients Who Received Liver and Splenic Stimulation

Hours After No. of Paired Mean Phagocytic Index Treatment Observations Baseline After Treatment 95% CI P Value

1 11 4.22 5.68 −2.108 to −0.815 .001

2 5 4.13 5.31 −1.710 to −0.650 .003

3 11 4.22 4.63 −0.986 to 0.168 .145

4 9 4.32 4.39 −0.727 to 0.576 .796

5 5 4.28 4.21 −0.280 to 0.404 .641

6 2 4.20 3.43 −5.769 to 7.319 .373

ducts. The operator would apply a rhythmic motion by populations, and pro-inflammatory cytokines. Castlio alternating pressure and release on the thorax, causing and Ferris-Swift found that splenic pumping had rela- the lymphatic ducts to empty when the thorax was de- tively little effect on the percentages of peripheral leu- pressed and to fill again when the pressure was re- kocyte cell types.18,19 In a study of 12 healthy medical leased.21 Miller coined the term thoracic pump to students (7 treatment, 5 control), pectoral traction with describe this technique.21 Other variations were splenic pumping caused a transient rise in basophils quickly developed and are collectively known today as relative to controls, but all other white blood cell types lymphatic pump techniques. in peripheral circulation were not affected.27 In another Lymphatic pumping improved the antibody response study of 20 relatively immobile nursing home residents, to pneumococcal polysaccharide vaccine in healthy male an OMT protocol had no effect on the percentages of medical students.22 Hepatitis B vaccine antibody titers white blood cell types present in peripheral circulation, rose faster in a group receiving lymphatic and splenic but 30 minutes after treatment the platelet counts were pump techniques.23 Dery et al24 were the first to use a rat significantly reduced in the OMT group relative to the model to show that rhythmic mechanical pressure in one sham group.28 Notable but insignificant decreases were region of the body enhanced lymph uptake in a distant found in the hemoglobin level, hematocrit level, red region. Later, a dog model was developed that showed blood cell count, and absolute number of lymphocyte the flow of lymph through the thoracic duct increased by cells in the OMT group.28 An OMT protocol that used both abdominal and thoracic pumping, somewhat similar hepatic, splenic, and lymphatic pump techniques in to what treadmill exercise achieves.25 Abdominal lym- healthy adults failed to show any between-group differ- phatic pumping in the dog model increased both the flow ences in total and differential white blood cell counts at of lymph moving through the thoracic duct and the 5, 30, and 60 minutes after treatment relative to a sham number of leukocytes in the thoracic lymph, thus greatly control.29 However, the OMT protocol induced a sig- increasing the flux of leukocytes moving through the nificant decrease in the proportion of a subpopulation of thoracic duct.26 blood dendritic cells and increased levels of granulo- Lymphatic pump techniques may have little imme- cyte–colony-stimulating factor and monocyte chemo- diate effect on the peripheral white blood cell count tactic protein-1 (MCP-1) cytokines after treatment differentials, but they affect platelet counts, sub-cell relative to the sham control.29

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Four minutes of lymphatic pump treatment in the Clinical Trial Evidence dog model significantly increased the flux of these -in In the early 1960s, Kline34 conducted the first random- flammatory mediators from body tissues, through the ized controlled trial of OMT as an added intervention to thoracic lymphatic duct, and into the blood.30 Specifi- antibiotics. He randomly assigned 252 children hospi- cally, lymphatic pump treatment increased the flux of talized for various respiratory tract infections into 1 of interleukin (IL)-6, IL-8, IL-10, MCP-1, and keratino- 3 groups: the first group received OMT, the second cyte chemoattractant in both the mesenteric and tho- group received antibiotics, and the third group received racic duct lymph. The flux through the thoracic OMT plus antibiotics. All patients received supportive lymphatic duct of IL-6 increased by 615%, IL-8 by care such as respiratory treatments and intravenous 944%, IL-10 by 917%, MCP-1 by 1505%, and kerati- fluid support. The OMT in this study consisted of reg- nocyte chemoattractant by 788% relative to pretreat- ular rib raising sessions that varied in frequency by the ment baseline. Also, the concentration of MCP-1 during age of the patient and apparently did not involve lym- treatment was increased in the thoracic duct lymph rela- phatic pump treatments. The mean hospital length of tive to pretreatment baseline.30 stay (LOS) was 6.3 days for the OMT group, 5.8 days Rats that were nasally infected with Streptococcal for the antibiotic treatment group, and 4.8 days for the pneumoniae and treated with a lymphatic pump daily OMT plus antibiotic treatment group, suggesting that for 7 consecutive days had significantly fewer col- OMT complements antibiotic therapy.34 This clinical ony-forming units in the lungs 8 days after infection trial compared OMT, antibiotics, and OMT with antibi- relative to control and sham therapy groups.31 In a otics and showed that OMT alone was not as good as similar study, rats given lymphatic pump treatments antibiotics alone, but the combination was better than 3 times per day for 3 consecutive days had signifi- either alone. A limitation of this study was that the sta- cantly fewer S pneumoniae colony-forming units in tistical significance of these differences in mean LOS the lungs relative to control and sham therapy.32 In a was not reported. third rat study, 3 applications of the lymphatic pump A controlled trial of 57 children with a history of at 24, 48, and 72 hours after inoculation with S pneu- 3 episodes of otitis media in the past 6 months found moniae significantly reduced the concentration of that adjunctive OMT significantly reduced the number bacteria in the lungs at 96 hours after inoculation of recurrent otitis media episodes and the need for sur- relative to both control and sham therapy groups.33 gical procedures relative to routine pediatric care.35 In a Treatment with levofloxacin cleared bacteria from clinical trial of 22 nursing home residents who received the lungs significantly better at 48, 72, and 96 hours their annual influenza vaccine the first week of October, after inoculation relative to a saline control, regard- patients received 10 treatment sessions of either OMT less of receiving sham or lymphatic pump therapy. or sham treatment over 4 weeks.36 The treatment group However, when 3 applications of lymphatic pump received a semistandardized 15-minute OMT protocol technique given at 24, 28, and 72 hours after inocula- that included paraspinal muscle inhibition, rib raising, tion were added to levofloxacin therapy, then bac- to the thoracic inlet, myofascial re- teria was cleared from the lungs significantly better lease to the diaphragm, thoracic lymphatic pump with than all other intervention groups.33 This study33 activation, and splenic pump. The sham treatment pro- provided, to my knowledge, the first direct evidence tocol consisted of light touch applied to the same ana- that the lymphatic pump technique worked synergis- tomic areas for approximately the same duration as the tically with antimicrobials. OMT protocol. This sham protocol was effective for

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introducing uncertainty of group assignment among the for the OMT group, 3.7 days for the light touch group, study participants.37 At the end of the study, participants and 3.9 days for the conventional care only group). were asked which group they thought they were in; Those patients who received OMT twice daily for the 43% of participants in both groups said the OMT group, duration of their hospital stay had lower all-cause mor- and the rest of the participants said they were unsure. tality and respiratory failure rates compared with those Although OMT failed to improve immunoglobulin who received conventional care.40 (Ig) M and IgG antibody titers 1, 2, 3, and 4 weeks after vaccination relative to the sham group, the mean total days receiving antibiotics from October through March Therapeutic Mobilization was significantly reduced in the OMT group (10.7 days In MOPSE, the light touch group outcomes often fell for the OMT group and 25.0 days for the sham group).36 between OMT and conventional care only groups, not The month with the most significant difference in mean being statistically different from either, making inter- days receiving antibiotics was January: 0.9 days for the pretation problematic. Other studies that used a 3-group OMT group and 5.5 days for the sham group. In another study design (treatment, sham, and usual care only study involving nursing home residents, twice-monthly groups) have reported similar outcomes.33,38 This out- OMT and sham treatments over 5 months reduced the come pattern is hard to explain. One explanation is that number of all-cause hospitalizations relative to a third sham protocols can create an early mobilization effect. treat-as-usual group.38 For example, in MOPSE, being in the sham light touch A randomized controlled trial of 21 elderly patients group meant more frequent changes in position were hospitalized for pneumonia found a mean LOS of required to accommodate the twice-daily protocol treat- 13.5 days for the OMT group and 15.8 days for the con- ments, whereas being in the conventional care only trol group, but the difference was not statistically signifi- group meant no extra mobilization. The light touch cant.39 In a larger study of 58 elderly patients hospitalized protocol was given in bed, so patients who were out of for pneumonia, OMT significantly reduced the mean bed had to get back in bed. Once in bed, the patients LOS and number of days receiving intravenous antibi- were further shifted about for treatment, and afterward otics.39 The mean LOS for the OMT group was 6.6 days the patients were free to get out of bed. A modest vs 8.1 days in the conventional care only group. In the amount of increased mobilization has a surprisingly treatment group, OMT reduced duration of intravenous significant effect. In one clinical trial, the simple inter- antibiotics by 2 days and reduced total duration of all vention of having patients with community-acquired antibiotics in the hospital by 3 days.39 pneumonia get out of bed from day 1 of their hospital The Multicenter Osteopathic Pneumonia Study in stay for 20 minutes per day resulted in a small but sig- the Elderly (MOPSE) showed that patients aged 50 nificant reduction in LOS.41 years or older who received a standardized OMT pro- Early mobilization refers to the application of phys- tocol had a statistically significant reduction in LOS ical activity, either active or passive, within the first few relative to those who received conventional care only.40 days of the hospital stay.42 A recent review of the litera- The mean LOS was 4 days for the OMT group, 4.4 days ture found that for adult patients in the intensive care for a light touch group, and 4.5 days for the conven- unit, early mobilization resulted in fewer ventilator-de- tional care only group. The mean duration of intrave- pendent days, shorter stays in the intensive care unit and nous antibiotics was likewise reduced in the OMT hospital, and better functional outcomes.43 Passive mo- group relative to the conventional care group (3.4 days tion of the legs for just 20 minutes in adult intubated pa-

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tients reduced pain and lowered serum IL-6 levels.44 In ventilation, number of days in the intensive care unit, or MOPSE, the 15-minute, twice daily protocol treatments hospital mortality.52 Limitations of rotational bed therapy may have similar effects to other early mobilization strat- included poor tolerance (patients generally need to be egies, with the light touch protocol representing a lesser unconscious) and interference with nursing care. A major degree of mobilization and OMT representing a greater difference between rotational bed therapy and osteo- degree of mobilization. Clinical trials of OMT in pneu- pathic lymphatic pump techniques is that rotational beds monia suggest that it is well tolerated, even in severely ill slowly rotate around the longitudinal axis, whereas lym- and frail elderly patients.39,40,45 Pedal and thoracic lym- phatic pump techniques generally move the patient back phatic pump techniques do not adversely change intra- and forth in a craniocaudal direction, which should be cranial pressure or cerebral perfusion pressure in patients much better for lymphatic circulation. with traumatic brain injuries.46 Osteopathic manipulative A lesser-known mechanical technique termed whole treatment has the potential of mobilizing patients who body periodic acceleration (WBPA) uses a motorized are too impaired to get out of bed. platform (a mechanical bed) that moves the patient, Immobility is associated with poor outcomes from who lies supine on the device, in a repetitive, sinu- infectious diseases. Bedfast nursing home residents are soidal, craniocaudal direction.53 This device produces a twice as likely to develop urinary tract infections, 2.5 body motion very similar to what is achieved by the times more likely to develop pneumonia, and 4 times osteopathic pedal pump. It has primarily been studied more likely to die of an infectious disease than nonbed- (using animal models) as an alternative to traditional fast nursing home residents.47 Multivariate analysis has compressive cardiopulmonary resuscitation and ap- shown that the greatest single predictor of mortality from pears to be effective in limiting damage to the myocar- pneumonia in elderly persons is immobility, with a very dium after cardiac arrest.43,54,55 The device also produces high OR of 9.4.48 For elderly residents of long-term care neurotherapeutic effects in the myocardium and pre- facilities, immobility was found to be a major risk factor serves heart rate variability after cardiac arrest.56,57 Ro- for other types of lower respiratory tract infections be- kutanda et al58 found that WBPA increased blood supply sides pneumonia.49 Implementing a protocol to progres- in ischemic lower extremities through activation of sively improve mobility daily in a neurointensive care endothelial nitric oxide synthase signaling and upregu- unit reduces LOS in the unit and hospital, number of lation of proangiogenic growth factor. It is believed that hospital-acquired infections, and number of ventilator- the pulsatile shear stress to the endothelium generated associated pneumonias.50 by WBPA stimulates nitric oxide production and vaso- A few mechanical devices have been developed to dilatation in healthy patients as well as in those with mobilize immobile patients. The best known is rotational inflammatory diseases.59 One published abstract re- bed therapy (also known as kinetic therapy), which con- ported that osteopathic pedal pump also increased sists of using a programmable bed that turns on its longi- serum nitric oxide levels.60 However, WBPA has yet to tudinal axis either continually or intermittently, between be studied for its effects on the lymphatic and human 25° to 65°. Rotational bed therapy decreases the inci- immune system. dence of infections, pneumonia, sepsis, and urinary tract infections.51 A meta-analysis of 35 studies between 1987 and 2004 suggested that rotational bed therapy in se- Discussion lected critically ill patients decreased the incident of Sometime near the close of the 19th century, Still was pneumonia but had no effect on duration of mechanical asked by a student if there were any infectious diseases

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that the body was unable to destroy alone. By implica- References

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19. Noll DR, Johnson JC, Brooks JE. Revisiting Castlio and 34. Kline CA. Osteopathic manipulative therapy, antibiotics, Ferris-Swift’s experiments on direct splenic stimulation and supportive therapy in respiratory infections in children: in patients with acute infectious disease. J Am Osteopath Assoc. comparative study. J Am Osteopath Assoc. 1965;65(3):278-281. 2008;108(2):71-79. 35. Mills MV, Henley CE, Barnes LL, Carreiro JE, Degenhardt BF. 20. Miller CE. Osteopathic treatment of acute infections by means The use of osteopathic manipulative treatment as adjuvant of the lymphatics. J Am Osteopath Assoc. 1920;19:494-499. therapy in children with recurrent acute otitis media. Arch Pediatr Adolesc Med. 2003;157(9):861-866. 21. Miller CE. The specific cure of pneumonia. J Am Osteopath Assoc. 1927;27(9):35-38. 36. Noll DR, Degenhardt BF, Stuart MK, Werden S, McGovern RJ, Johnson JC. The effect of osteopathic manipulative treatment 22. 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55. Adams JA, Uryash A, Wu H, et al. Microcirculatory and 63. Goldstein M. Osteopathic manipulative treatment therapeutic effects of whole body periodic acceleration (pGz) for pneumonia. Osteopath Med Prim Care. 2010;4(1):3. applied after cardiac arrest in pigs. Resuscitation. 2011;82(6): doi:10.1186/1750-4732-4-3. 767-775. doi:10.1016/j.resuscitation.2011.02.012. 64. Noll DR. Response [letter]. J Am Osteopath Assoc. 56. Adams JA, Uryash A, Bassuk J, Sackner MA, Kurlansky P. 2014;114(2):81-82. doi:10.7556/jaoa.2014.019. Biological basis of neuroprotection and neurotherapeutic effects 65. Noll DR. Evidence-based medicine and osteopathic of Whole Body Periodic Acceleration (pGz). Med Hypotheses. medicine: no paradox. J Am Osteopath Assoc. 2014;82(6):681-687. doi:10.1016/j.mehy.2014.02.031. 2015;115(3):124-125. doi:10.7556/jaoa.2015.024. 57. Adams JA, Uryash A, Nadkarni V, Berg RA, Lopez JR. © 2016 American Osteopathic Association Whole body periodic acceleration (pGz) preserves

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608 The Journal of the American Osteopathic Association September 2016 | Vol 116 | No. 9