The sickle cell diseases (SCDs) affect approximately

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1 o r i g i n l c o m m u n i c t i o n Pin Mngement in Adults With Sickle Cell Disese in Medicl Center Emergency Deprtment Lwrence R. Solomon, MD Previous Presenttion: This pper ws presented in prt in bstrct form (Blood. 2007;110: Abstrct 2267) nd s poster t the 49th nnul meeting of the Americn Society of Hemtology, Atlnt, Georgi, December 10, Guidelines for pin mngement in dult sickle cell ptients with vso-occlusive crises suggest prompt, frequent dministrtion of prenterl opioids. Neither the bility to implement these guidelines in busy urbn emergency deprtment nor opioid dose requirements in uncomplicted vso-occlusive crisis hve been previously documented. Thus, retrospective review of vso-occlusive crisis treted in n urbn medicl center emergency deprtment in 2005 ws performed to define opioid requirements nd brriers to guideline implementtion. Fifty-seven visits by 19 ptients were evluble. Opioid tretment ws not initited for more thn 2 hours during 30% of visits; the intervl between the first nd second opioid doses exceeded 1 hour in 26% of visits nd incresed with subsequent doses; nd totl tretment time ws less thn 1 hour during 21% of visits (medin, 2.2 hours). Opioid doses (s intrvenous morphine equivlents) rnged from 4 to 26.7 mg ( mg/kg) nd exceeded 10 mg during 40 visits (70%) nd in 10 ptients (53%). Hospitliztion occurred on 25 occsions with 48% of ptients dmitted fter 3 or fewer opioid doses nd 50% of ptients dmitted fter less thn 3 hours of tretment. Moreover, return emergency deprtment visits occurred within 3 dys fter 9 of 32 home dischrges (28%) with tretment times uniformly less thn 3 hours during the preceding visit. It is concluded tht: (1) opioid dose requirements vry widely, often exceeding guideline recommendtions; nd (2) tretment time nd timely opioid dministrtion re often compromised, resulting in delyed pin control nd premture decisions on disposition with erly return visits nd possibly voidble hospitl dmissions. Keywords: pin n Sickle cell disese J Ntl Med Assoc. 2010;102: Author Affilitions: Adult Sickle Cell Disese Progrm, Sections of Hemtology nd Pllitive Cre, Deprtment of Medicine, Yle University School of Medicine, New Hven, Connecticut. Correspondence: Lwrence R. Solomon, MD, Adult Sickle Cell Disese Progrm, Sections of Hemtology nd Pllitive Cre, Deprtment of Medicine, Yle University School of Medicine, 333 Cedr St, PO Box , New Hven, CT (lwrence.solomon@yle.edu). INTRODUCTION The sickle cell diseses (SCDs) ffect pproximtely individuls in the United Sttes, mny of whom suffer frequent vso-occlusive crises with severe pin often requiring prenterl opioid dministrtion in hospitl emergency deprtments nd inptient units. 1-7 Guidelines for pin mngement in SCD, developed in the United Sttes nd the United Kingdom, suggest: (1) prompt initition of prenterl opioids; (2) use of effective opioid doses; (3) repet opioid doses t frequent intervls; nd (4) individuliztion of tretment bsed on prior opioid response histories (Tble 1) However, effective nd timely tretment of pin in emergency deprtments is often limited Moreover, lck of wreness of vilble guidelines nd continuing ethnic disprities in pin tretment in emergency deprtment settings further compromise cre. 14,15 Finlly, opioid requirements of dult SCD ptients during emergency deprtments visits re not well defined nd fctors tht cn modify tretment decisions, including liver nd renl dysfunction (which lter opioid metbolism), chronic long-cting opioid use or substnce buse (which induce both opioid tolernce nd hyperlgesi), nd the presence of other cute illnesses (which my led to more prompt evlution nd hospitl dmission), hve not been considered Since clinicl profiles of ptients followed by the Yle Adult Sickle Cell Progrm re vilble for the identifiction of ptients with significnt confounding comorbidities, nd since protocol similr to vilble guidelines hs been used in the Yle New Hven Hospitl (YNHH, Connecticut) emergency deprtment (Tble 1), retrospective review ws performed s qulity-improvement inititive to determine if these stndrds were effectively implemented nd to define opioid dose requirements. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER

2 METHODS All emergency deprtment visits between Jnury 1, 2005, nd December 31, 2005, by the 83 ptients with SCD followed by the Adult Sickle Cell Progrm of the Yle University School of Medicine were reviewed. Time of trige, time of ccess to bed, opioid doses nd their times of dministrtion, nd time of finl disposition were recorded. The totl tretment time, defined s the time between the first nd lst opioid doses, ws lso clculted. All ptients received either morphine or hydromorphone intrvenously, nd doses were expressed in terms of intrvenous (IV) morphine equivlents with conversion fctor of 1.5 mg of IV hydromorphone to 10 mg of IV morphine. 20 Ptient weights were those t the time of dmission or in the outptient clinic within 4 weeks of emergency deprtment evlution. Forty-one ptients (49%) were not seen in the emergency deprtment during this period. Another 15 ptients (18%) with 135 emergency deprtment visits were excluded becuse of the dily use of orl long-cting opioids. The remining 27 ptients hd 87 emergency deprtment visits. Five of these ptients with 12 emergency deprtment visits were excluded becuse of known liver disese (chronic heptitis B or heptitis C in 4 ptients nd cirrhosis of unknown cuse in 1 ptient). Two dditionl visits were inevluble becuse of either the filure to document opioid doses or the determintion tht pin ws not due to vso-occlusive crisis. Of the remining 73 emergency deprtment visits by 22 ptients, the decision to hospitlize the ptient ws considered to be relted to comorbid complictions on 16 occsions (fever or documented infection on 10 visits; hypoxi on 2 visits; nd pregnncy, renl ppillry necrosis, splenic infrction, nd suspected pulmonry embolism on 1 visit ech). The remining 57 visits by 19 ptients were thus considered to represent Figure 1. Emergency Deprtment Visits of Adult Sickle Cell Ptients t Yle New Hven Hospitl (YNHH) During YNHH Adult Sickle Cell Registry (N = 83 Ptients) Emergency Deprtment Visits No Emergency Deprtment Visits (N = 42 Ptients, 51%) (N = 41 Ptients, 49%) Using Dily Not Using Long-cting Opioids Long-cting Opioids 15 Ptients, 135 Visits 27 Ptients, 87 Visits Admissions, 104 (77%) Admissions, 55 (63%) Exclusions Evluble 14 Visits 22 Ptients, 73 Visits Admitted Home (13 Ptients, 32 Visits) Comorbid Complictions 16 Visits No Complictions (12 Ptients, 25 Visits) Uncomplicted VOC 19 Ptients, 57 Visits Admissions, 25 (43%) Abbrevition: VOC, vso-occlusive crisis. See Methods for detils of ptient exclusions nd list of comorbidities contributing to dmission JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER 2010

3 uncomplicted vso-occlusive crisis (Figure 1). None of these ptients exhibited behviors suggestive of substnce buse using the criteri of Svge, nd serum cretinine vlues were norml in ll of them. 21 Differences between vlues were nlyzed by 2-sided Student t tests or c 2 distribution nlyses. 22 The institutionl humn investigtion committee determined tht this study did not require institutionl review bord pprovl. RESULTS Ptient Chrcteristics Fourteen of the 19 ptients were women (74%). Eleven hd the SS genotype (58%), 5 were SC (26%), nd 3 were S-ß thlssemi (16%). The medin ge ws 28 yers (rnge, yers). Twelve ptients (65%) hd 1 to 2 emergency deprtment visits tht met study criteri; 3 ptients hd 3 visits ech (16%); nd 4 ptients hd 5 or more visits ech (26%), including 2 ptients with 5 visits ech, 1 ptient with 6 visits, nd 1 ptient with 16 visits (medin, 2.0 visits/ptient/yer). Outcomes of Emergency Deprtment Visits Twenty-five visits (44%) ended in hospitliztion. Hospitliztion ws no more frequent in the 7 ptients seen on 3 or more occsions (17 of 41 visits, 41%) thn in the 12 ptients seen on only 1 or 2 occsions (8 of 16 visits, 50%)(c 2 = 0.353, nonsignificnt). Ptients returned home fter the remining 32 visits but revisited the emergency deprtment within 3 dys on 9 occsions (28%). Durtion of Tretment nd Frequency of Opioid Administrtion The totl time in the emergency deprtment (from trige to disposition) ws known for 44 of the 57 evluble visits nd rnged from 1.4 to 17.8 hours (medin, 5.1 h). Visits lsted less then 4 hours on 11 occsions (25%) nd longer thn 8 hours on 5 occsions (11%). In contrst, the totl tretment time ws only 2.9 ± 2.6 hours (medin, 2.2 h; rnge, h) during the 53 visits in which this could be determined. In fct, tretment ws given for less thn 1 hour during 11 of these visits (21%) (Tble 2). Similrly, ptients received between 1 nd 9 opioid doses (medin, 3.0 doses), but mximum of only 2 doses were given on 15 occsions (27%) (Tble 2). Of the 25 visits ending in hospitliztion, mximum of 3 opioid doses were given on 12 occsions (48%) with 1 ptient dmitted fter only 1 dose nd 2 ptients dmitted fter only 2 doses. Totl tretment time ws no more thn 3 hours on 11 of 22 evluble visits (50%) nd no more thn 1 hour on 5 occsions (23%) (Tble 2). Of the 32 visits ending in dischrge home, mximum of 3 opioid doses were given on 27 occsions (87%) nd totl tretment time ws less thn 2 hours on 18 occsions (55%). Return to the emergency deprtment within 3 dys occurred on 9 occsions (28%) nd tretment times were less thn 2 hours during 6 of the preceding visits (67%), with no more thn 3 opioid doses given during 8 of them (89%). Doses of Opioid Administered The initil opioid ws morphine (4-10 mg) on 23 occsions nd hydromorphone (1-2 mg) on 34 occsions. The 7 ptients with 3 or more visits received the sme initil opioid dose on 34 of their 41 visits (83%). The totl cumultive opioid dose ws 43 ± 31 mg/ visit (rnge, mg/visit). The usul initil opioid dose in these 19 individuls (defined s the dose most often used in ptients with multiple visits or the highest dose dministered in ptients with 2 visits) vried from 4 to 13.3 mg (medin, 10.0 mg). This dose ws no more thn 5 mg for 6 ptients (32%) but exceeded 10 mg for 7 ptients (37%). The mximum single dose dministered t ny time to ech of the 19 individul ptients rnged from 4 to 26.7 mg (medin, 13.3 mg). Overll, single doses exceeded 10 mg on t lest 1 occsion during 40 of the 57 visits (70%) nd in 10 of the 19 ptients (53%). Five ptients (26%) received dose of 26.7 mg (equivlent to 4.0 mg of intrvenous hydromorphone). Weight-Bsed Opioid Doses Weight-bsed opioid dosing ws not used in the YNHH emergency deprtment but hs been suggested in Tble 1. Guidelines for the Tretment of Pin Due to Vso-occlusive Crisis in Adults With Sickle Cell Disese Time to Prenterl Opioid Guideline First Dose Dose Frequency Individulize Americn Pin Society/Ntionl Institutes min 5-10 mg morphine or min Yes of Helth 1.5 mg hydromorphone British Hemtology Tsk Force b <30 min 0.1 mg/kg morphine <20 min Yes Yle New Hven Hospitl emergency deprtment Prompt 4-8 mg morphine 10 min Not stted Doses given re for dults weighing >50 kg. Doses for dults weighing <50 kg re 0.1 mg/kg of morphine or mg/kg hydromorphone. Subsequent doses re one-qurter to one-hlf of the initil dose titrted for pin relief bsed on ptient response. b The sme dose used initilly is repeted t lest every 20 minutes s needed. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER

4 mny cute pin scenrios, including the UK guidelines for vso-occlusive crisis. 9 Thus, weight-bsed doses were lso clculted. The usul initil weight-bsed opioid dose rnged from 0.05 to 0.28 mg/kg (medin, 0.14 mg/ kg). This dose ws less thn 0.1 mg/kg in 7 ptients (37%) but exceeded 0.15 mg/kg in 8 ptients (42%) (Tble 4). The mximum weight-bsed dose dministered t ny time to ech individul ptient rnged from 0.05 to 0.50 mg/kg (medin, 0.19 mg/kg), with doses exceeding 0.15 mg/kg given to 10 ptients (53%) (Tble 3). Visit Frequency nd Opioid Doses More frequent visitors received higher opioid doses. Thus, the usul initil dose in the 7 ptients seen on 3 or more occsions ws 12.4 ± 1.6 mg, while the 12 ptients with only 1 to 2 visits received only 8.0 ± 3.5 mg (p <.01). In fct, 5 of the 7 ptients with 3 or more emergency deprtment visits received initil doses of t lest 13.3 mg (71%) nd 4 of them received mximum doses of 26.7 mg (57%). In contrst, only 2 of the 12 ptients with 1 to 2 emergency deprtment visits received initil doses of 13.3 mg (17%), nd only 1 received mximum dose of 26.7 mg (8%) (c 2 = 5.591, p <.02) (Figures 2A nd 2B). Similrly, only 10 of the 56 doses dministered to ptients with 1 to 2 emergency deprtment visits were greter thn 10 mg (18%), wheres 105 of the 133 doses given to ptients with 3 or more emergency deprtment visits exceeded 10 mg (79%) (c 2 = , p <.001) (Figure 2C). The findings were similr using weight-bsed opioid doses (dt not shown). Titrtion of Opioid Dose At lest 3 opioid doses were given during 42 emergency deprtment visits. Doses were unchnged during 23 of these visits (55%), incresed during 14 visits (33%), nd decresed during 5 visits (12%). Doses were more likely to be incresed if initil doses were no greter thn 6.7 mg (7 of 9 visits, 78%) thn if initil doses were t lest 10 mg (7 of 33 visits, 21%, c 2 = , p <.002). Of the 5 visits in which opioid doses were decresed, initil doses were equl to or greter thn 13.3 mg in 4 of them (80%), nd doses were lter incresed gin on 2 occsions. Thus, of the 25 visits where the initil opioid dose ws t lest 13.3 mg, subsequent opioid doses were the sme or higher on 23 occsions (92%). In fct, the finl dose ws the sme during ll 4 visits where n initil opioid dose of t lest 20 mg ws dministered. Timing of Opioid Doses The medin time from trige to initition of opioid therpy ws 70 minutes (Tble 4). Ptients were treted within 30 minutes during only 18% of visits, while tretment ws not initited for t lest 2 hours during 30% of visits. The longer delys in initition of therpy were usully due to limited bed vilbility. Thus, the medin time from trige to ccess to n emergency deprtment bed ws 48 minutes, with 20 of 49 evluble visits requiring more thn 1 hour (41%) nd 10 visits requiring more thn 2 hours (20%). In contrst, the medin time between ccess to n emergency deprtment bed nd the dministrtion of the first opioid dose ws 24 minutes, with only 5 of 48 visits requiring more thn 1 hour (10%). The time between opioid doses exceeded 30 minutes during more thn 70% of visits nd incresed progressively with ech successive opioid dose. Thus, the time between doses exceeded 1 hour during 26% of visits for doses 1 to 2, 51% of visits for doses 2 to 3, nd 61% of visits for doses 3 to 4. Tble 2. Opioid Doses nd Totl Tretment Time During Emergency Deprtment Visits for Uncomplicted Vso-occlusive Crisis Disposition Criterion No. of doses >4 Tretment time, h c < >5 Admit Home All 3/25 (12%) 9/25 (36%) 6/25 (24%) 7/25 (28%) 5/22 (23%) 2/22 (9%) 4/22 (18%) 2/22 (9%) 4/22 (18%) 5/22 (23%) 12/32 (38%) 15/32 (47%) 5/32 (16%) 0/32 (0%) 6/31 (19%) 11/31 (36%) 10/31 (32%) 2/31 (6%) 2/31 (6%) 0/31 (0%) 15/57 b (26%) 24/57 (42%) 11/57 (19%) 7/57 (12%) 11/53 (21%) 13/53 (25%) 14/53 (26%) 4/53 (8%) 6/53 (11%) 5/53 (9%) The number of opioid doses dministered ws evluble for ll 57 emergency deprtment visits. b One ptient who ws dmitted to the hospitl received 1 opioid dose nd the other 14 ptients received 2 opioid doses ech. c Tretment time ws defined s the time intervl between the first opioid dose nd the lst opioid dose. This ws not known for 3 visits ending in inptient dmission nd 1 visit ending in dischrge to home JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER 2010

5 Fctors Affecting the Timing of Opioid Doses Time of dy. Ptients seen during hours when the emergency deprtment is usully less busy (2 AM-12 PM) hd ccess to bed sooner nd received their first opioid dose more promptly thn ptients seen during the hours when emergency deprtment utiliztion is usully the gretest (2-8PM) (Tble 5). Nonetheless, ptients seen in the erly morning hours were not treted for longer period of time (men, 157 vs 156 h), did not receive greter number of opioid doses (men 3.7 vs 3.2 doses), nd were not dmitted to the hospitl ny less frequently (62% vs 43%) thn ptients seen during the busy fternoon hours. Frequency of emergency deprtment visits. Ptients seen in the emergency deprtment more frequently (3 or more visits per yer) did not receive more prompt ttention thn those seen less often (1-2 visits/yer). In fct, dosing intervls were ctully longer in the former group (Tble 5). The intervls between the second nd third opioid doses nd between the third nd fourth opioid doses were lso more likely to exceed 60 minutes in ptients seen on 3 or more occsions (18 of 28, 64% nd 11 of 12, 92%, respectively) thn in ptients seen less frequently (2 of 11, 18% nd 1 of 6, 17% respectively)(c 2 = nd , p =.012 nd <.001). However, totl tretment times (men, 125 vs 166 h), numbers of opioid doses (men, 3.5 vs 3.2 h), nd rtes of hospitliztion (50% vs 41%) were the sme in ptients seen on only 1 or 2 occsions s in those seen more frequently. DISCUSSION Vso-occlusive crises in dult SCD ptients re the most common cuse of recurrent ptient visits to the emergency deprtment for the specific tretment of pin. Nonetheless, there is limited wreness of existing guidelines for the mngement of this disorder. 8-10,15 Moreover, informtion on the bility to implement these guidelines, the impct of their utiliztion, nd the ctul opioid dose requirements of dult SCD ptients is lso limited. PAIN IN SICKLE CELL DISEASE Figure 2. Frequency of Emergency Deprtment Visits nd Opioid Dose Requirements A, Visit Frequency nd Usul Initil Opioid Dose Visits (N = 12) 3 Visits (N = 7) 10 mg 13.3 mg Intrvenous Morphine Equivlents B, Visit Frequency nd Mximum Opioid Dose mg 1-2 Visits (N = 12) 3 Visits (N = 7) 5 mg 10 mg 13.3 mg Intrvenous Morphine Equivlents C, Visit Frequency nd All Opioid Doses Visits (56 Doses) 3 Visits (133 Doses) 26.7 mg 6.7 mg 10 mg 13.3 mg 20 mg Intrvenous Morphine Equivlents The usul initil opioid dose (A) nd the mximum opioid dose required during ny visit (B) re shown for the 12 ptients with 1-2 emergency deprtment visits nd for the 7 ptients with 3 or more emergency deprtment visits during the study yer. The distribution of ll opioid doses received by these ptients during ll visits re lso shown (C). Usul initil opioid dose nd intrvenous morphine equivlents re defined in the Methods. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER

6 Thus, of 6 prior studies: 2 were protocol studies compring different opioid regimens, time required for the initition of opioid therpy ws only reported in 1 study, no study reported the time intervls between subsequent opioid doses, nd ctul opioid doses nd tretment times were only reported in 1 of the protocol studies Finlly, no study considered the impct of renl nd liver dysfunction on ptient opioid requirements, nd only the 2 protocol studies specificlly excluded ptients with history of drug buse or possible opioid tolernce. In the present study, only emergency deprtment visits by ptients without other cute comorbidities or confounding medicl disorders were evluted. The most striking findings were: (1) gret interindividul vribility of opioid dose requirements with the frequent need for doses exceeding guideline recommendtions; (2) long delys in the initition of opioid therpy nd in the dministrtion of subsequent opioid doses; nd (3) short totl tretment times prior to decision on disposition. Opioid doses used in individul ptients vried widely (Tble 3), finding consistent with previous reports nd with the known interindividul vribility in morphine phrmcokinetics. 24,29-33 Moreover, 53% of ptients received doses exceeding either the Americn Pin Society/Ntionl Institutes of Helth guideline of 10 mg or the British Hemtology Tsk Force guideline of 0.1 mg/kg (Tble 3). Two observtions support the frequent need for higher opioid doses: (1) dose increses were required during 78% of visits in which the initil opioid dose ws less thn 10 mg, nd (2) ptients seen more frequently received higher initil opioid doses (Figure 2A). Ptients with more frequent visits hve Tble 3. Weight-Bsed Opioid Doses in 19 Individul Sickle Cell Ptients with Uncomplicted Vso-occlusive Crisis Opioid Dose (mg/kg Intrvenous Morphine Equivlents) < >0.30 Usul initil dose 7 (37%) 4 (21%) 2 (11%) 6 (32%) 0 (0%) Mximum dose 4 (21%) 5 (26%) 2 (11%) 3 (16%) 5 b (26%) The 7 lowest doses were 0.07 mg/kg in 3 ptients; nd 0.05, 0.06, 0.08, nd 0.09 mg/kg in 1 ptient ech. b The 5 highest doses were: 0.36, 0.39, 0.42, 0.42, nd 0.50 mg /kg in 1 ptient ech. Tble 4. Timing of Opioid Doses in Uncomplicted Vso-occlusive Crisis Time, min Trige to First Dose (N = 56) Trige to Bed (N = 49) Bed to First Dose (N = 48) First to Second Dose (N = 54) Second to Third Dose (N = 39) Third to Fourth Dose (N = 18) <30 10 (18%) 18 (37%) 32 (67%) 16 (30%) 6 (15%) 3 (17%) (27%) 11 (22%) 11 (23%) 24 (44%) 13 (33%) 4 (22%) (25%) 10 (20%) 5 (10%) 10 (19%) 14 (36%) 8 (44%) > (30%) 10 (20%) 0 (0%) 4 (7%) 6 (15%) 3 (17%) Medin (rnge) 70 min (7-410) 48 min (0-320) 24 min (0-90) 45 min (5-130) 65 min (10-345) 73 min (5-183) Includes time from trige to bed plus time from bed to first dose. Tble 5. Fctors Affecting Timing nd Frequency of Opioid Administrtion Time of Visit b Visit Frequency c Ctegory 2AM-12PM (N = 13) 2-8PM 1-2/yer (N = 21) p d (N = 16) 3/yer (N = 41) p d Trige to bed 32 ± 37 (N = 10) 85 ± 71 (N = 18) < ± 52 (N = 14) 77 ± 85 (N = 35) NS Bed to first dose 17 ± 19 (N = 10) 33 ± 20 (N = 18) < ± 25 (N = 14) 27 ± 21 (N = 34) NS First dose to second dose 51 ± 30 (N = 12) 55 ± 32 (N = 20) NS 38 ± 36 (N = 14) 60 ± 32 (N = 40).04 Second dose to third dose 68 ± 26 (N = 9) 101 ± 85 (N = 13) NS 52 ± 41 (N = 11) 94 ± 75 (N = 28).09 Third dose to fourth dose 90 ± 32 (N = 5) 93 ± 46 (N = 5) NS 57 ± 57 (N = 6) 87 ± 38 (N = 12) NS Abbrevition: NS, not significnt. Vlues re minutes given s the men ± 1 stndrd devition nd vlues in prentheses re number of visits included in ech determintion. b Time of visit compres the slow emergency deprtment hours (3AM-12PM) with busy ED hours (2-8PM). c Visit frequency compres ptients seen often ( 3 visits/yr) with those seen infrequently (1-2 visits/yr). d p vlues were determined by c 2 nlysis for dmissions nd 2-sided Student t test for ll other vlues JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER 2010

7 indeed been noted to hve more severe disese (by both lbortory nd qulity-of-life mesures), nd it is lso likely tht their opioid requirements were better estblished thn in ptients seen less frequently. 34 Underdosing of opioids is not unique to SCD since 0.15 mg/kg of intrvenous morphine ws found to be more effective thn 0.10 mg/kg in treting other cuses of pin in the emergency deprtment setting, nd even the 0.15 mg/kg regimen filed to produce significnt pin relief in 23% of ptients. 35 The importnce of inititing tretment with effective opioid doses is suggested by study in older children with SCD where the risk of hospitl dmission ws greter if the initil opioid dose hd miniml effect on the pin score. 36 The dely in the initition of opioid therpy is lso consistent with previous reports nd is best explined by the delys in ccess to n emergency deprtment bed, reflecting the hevy work lod in urbn centers (Tble 4) ,28 Thus, delys were greter during the hours when the emergency deprtment ws usully busiest, nd opioid dministrtion ws generlly prompt once the ptient ws in bed (Tbles 4 nd 5). Another fctor contributing to delys in inititing opioid therpy is the difficulty in obtining IV ccess. 28 Although this could not be quntified in the current study, informl discussions suggested tht both physicins nd ptients were generlly unwre of the effectiveness of subcutneous opioid dministrtion. However, even fter intrvenous ccess hd been estblished, the intervls between opioid doses usully exceeded guideline recommendtions nd incresed progressively with successive doses (Tbles 4 nd 5). This my reflect both unfmilirity with guideline recommendtions nd distrust of ptients (prticulrly frequent visitors) by emergency deprtment personnel ssocited with unwrrnted concerns bout ddiction nd drug-seeking behviors. 15 It is of note then, tht more frequent visitors in the current study ctully received less timely opioid dministrtion thn ptients seen less often (Tble 5). Similr to previous reports, 44% of emergency deprtment visits resulted in hospitliztion, while return to the emergency deprtment within 3 dys occurred fter 28% of the visits following dischrge to home. 24,26,36-38 Striking in this regrd were the short tretment times (medin, 2.2 hours) nd the fct tht no more thn 3 doses of opioids were dministered during 68% of visits. In fct, in survey of the Society of Acdemic Emergency Medicine, 25% of respondents considered sickle cell pin to be refrctory to therpy fter mximum of 2 opioid doses, nd 78% of respondents defined pin s refrctory fter mximum of 3 opioid doses. 39 In contrst, hospitliztion rtes fter tretment of uncomplicted vso-occlusive crisis in dy hospitl settings, where more timely nd protrcted opioid therpy is given, re consistently less thn 20% with erly revisit rtes of less thn 10%. 37,40,41 It is significnt then tht 30% of dy hospitl ptients required tretment for 2 to 4 hours nd n dditionl 10% of ptients did not chieve pin relief for 4 to 6 hours. 37 Moreover, frequent pin ptients ctully required longer tretment times to chieve pin relief. 37 Ineffective pin control prior to dischrge my lso contribute to high erly revisit rtes. Unfortuntely, pin scores were rrely recorded in the present study nd hve not been noted in prior reports. However, the filure to chieve significnt pin control during inptient mngement of vso-occlusive crisis hs been identified s cuse for erly redmission. 42 Finlly, mny ptients re nxious to leve the emergency deprtment nd express frustrtion with the cre they receive nd the long wits before nd during opioid therpy. 43 This frustrtion lso contributes to delys in visiting the emergency deprtment fter the onset of crisis, mking the gol of effective pin control ll the more difficult to chieve. 44 It is concluded tht opioid dose requirements vry widely in ptients with uncomplicted vso-occlusive crisis nd often exceed guideline recommendtions. Moreover, time constrints in the busy urbn emergency deprtment setting my result in delyed pin control nd premture decisions on disposition with erly emergency deprtment return visits nd possibly voidble hospitl dmissions. Attempts to improve emergency deprtment mngement of vso-occlusive crises should therefore focus on continued high prioritiztion trige of these ptients for rpid emergency deprtment ccess, physicin nd ptient eduction to increse use of subcutneous opioid dministrtion when IV ccess is limited, mintennce of records of individul ptient opioid requirements to enble initition of therpy t n pproprite dose, recognition of the need for more extended tretment times in ptients with frequent severe vso-occlusive crises, nd emergency deprtment protocols to encourge timely nd prolonged opioid dministrtion with defined pin score trget prior to dischrge. Acknowledgments The suggestions nd support of Genice Nelson, APRN, nd Ellen Dorm, LCSW, re grtefully cknowledged. REFERENCES 1. Steiner CA, Miller JL. Sickle cell disese ptients in US hospitls, HCUP Sttisticl Brief #21. December Nieter PJ, Silverstein MD, Abboud MR. Sickle cell nemi: epidemiology nd cost of illness. Phrmco Economics. 2002;20: Dvis H, Moore RM Jr, Gergen PJ. Cost of hospitliztions ssocited with sickle cell disese in the United Sttes. Public Helth Rep. 1997;112: Okumur MJ, Cmpbell AD, Nsr SZ, et l. Inptient helth cre use mong dult survivors of chronic childhood illnesses in the United Sttes. Arch Peditr Adolesc Med. 2006;160: Pltt OS, Brmbill DJ, Rosse WF, et l. Motlity in sickle cell disese life expectncy nd risk fctors for erly deth. New Engl J Med. 1994;330: Wiereng KJJ, Hmbleton IR, Lewis NA. Survivl estimtes for ptients JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER

8 with homozygous sickle-cell disese in Jmic: clinic-bsed popultion study. Lncet. 2001;357: Steiner CA, Miller JL. Sickle cell ptients in US hospitls, Sttisticl brief No. 2. Rockville, MD: Agency for Helthcre Reserch nd Qulity; December Benjmin LJ, Dmpier CD, Jcox AK, et l. Guideline for the mngement of cute nd chronic pin in sickle-cell disese. Glenville, IL: APS Clinicl Prctice Guideline Series, No. 1, Rees DC, Olujohunghe AD, Prker NE, et l. Guidelines for the mngement of the cute pinful crisis in sickle cell disese. Brit J Hemtol. 2003;120: Mngement of Sickle Cell Disese. NIH Publiction , 4th Ed. 2002: Grnt PS. Anlgesi delivery in the ED. Am J Emerg Med. 2006;24: Todd KH, Duchrme J, Choiniere M, et l. Pin in the emergency deprtment: results of the pin nd emergency medicine (PEMI) multicenter study. J Pin. 2007;8: Arendts G, Fry M. Fctors ssocited with dely to opite nlgesi in emergency deprtments. J Pin. 2006;9: Pletcher MJ, Kertesz SG, Kohn MA, et l. Trends in opioid prescribing by rce/ethnicity for ptients seeking cre in US emergency deprtments. JAMA. 2008;299: Solomon LR. Tretment nd prevention of pin due to vso-occlusive crises in dults with sickle cell disese: n eductionl void. Blood. 2008;111: Dvies G, Kingswood C, Street M. Phrmcokinetics of opioids in renl dysfunction. Clin Phrmcokinet. 1996;31: Tegeder I. Lotsch J, Geisslinger G. Phrmcokinetics of opioids in liver disese. Clin Phrmcokinet. 1999;37: Murphy EJ. Acute pin mngement phrmcology for the ptient with concurrent renl or heptic disese. Anesth Intensive Cre. 2005;33: Chng G, Chen L, Mo J. Opioid tolernce nd hyperlgesi. Med Clin N Am. 2007;91: Berdine HJ, Nesbit SA. Equinlgesic dosing of opioids. J Pin Pllitive Cre Phrmcother. 2006;20: Svge SR. Assessment for ddiction in pin-tretment settings. Clin J Pin. 2002;18(4suppl):S28-S Hill AB, Principles of Medicl Sttistics, 9th Ed. New York, NY: Oxford University Press; Gonzlez ER, Ornto JP, Wre D, et l. Comprison of intrmusculr nlgesic ctivity of butorphnol nd morphine in ptients with sickle cell disese. Ann Emerg Med. 1988;17: Gonzlez ER, Bhl N, Hnsen LA, et l. Intermittnt injection vs ptientcontrolled nlgesi for sickle cell crisis pin. Arch Int Med. 1991:151; Brookoff D, Polomn R. Treting sickle cell pin like cncer pin. Ann Int Med. 1992;116: Koshy M, Leikin J, Dorn L, et l. Evlution nd mngement of sickle cell disese in the emergency deprtment (n 18 yer experience): Am J Therpeutics. 1994;1: Givens M, Rutherford C, Joshi G, et l. Impct of n emergency deprtment pin mngement protocol on the pttern of visits of ptients with sickle cell disese. J Emerg Med. 2007;32: Tnbe P, Myers R, Zosel A, et l. Emergency deprtment mngement of cute pin episodes in sickle cell disese. Acd Emerg Med. 2007;14: Drbri DS, vn Schsik RHN, Cprelli EV, et l. UGT2B7 promoter vrint 840G>A contributes to the vribility in heptic clernce of morphine in ptients with sickle cell disese. Am J Hemtol. 2008;83: Drbri DS, Minniti CP, Rn S, et l. Phrmcogenetics of morphine: potentil pplictions in sickle cell disese. Am J Hemtol. 2008;83: Dmpier CD, Setty BNY, Logn J, et l. Intrvenous morphine phrmcokinetics in peditric ptients with sickle cell disese. J Peditr. 1995;126: vn Beers EJ, vn Tuijn CFJ, Nieuwkirk PT, et l. Ptient-controlled nlgesi versus continuous infusion of morphine during vso-occlusive crisis in sickle cell disese: rndomized controlled tril. Am J Hemtol. 2007;82: Shpiro BS, Cohen DE, Howe CJ. Ptient-controlled nlgesi for sicklecell-relted pin. J Pin Symptom Mnge. 1993;8: Aisiku IP, Smith WP, McClish DK, et l. Comprison of high vs low emergency deprtment utilizers in sickle cell disese. Ann Emerg Med. 2009;53: Birnbum A, Esses D, Bijur PE, et l. Rndomized double-blind plcebocontrolled tril of two intrvenous morphine doses (0.10 mg/kg nd0.15 mg/kg) in emergency deprtment ptients with moderte to severe pin. Ann Emerg Med. 2007;49: Frei-Jones MJ, Bxter AL, Rogers ZR, et l. Vso-occlusive episodes in older children with sickle cell disese: emergency deprtment mngement nd pin ssessment. J Peditr. 2008;152: Benjmin LJ, Swinson GI, Ngel RL. Sickle cell nemi dy hospitl: n pproch for the mngement of uncomplicted pinful crises. Blood. 2000;95: Epstein K, Yuen E, Riggio JM, et l. Utiliztion of the office, hospitl nd emergency deprtment for dult sickle cell ptients: 5 yer study. J Ntl Med Assoc. 2006;98: Slibergleit R, O Sullivn Jncis M, et l. Mngement of sickle cell pin crisis in the emergency deprtment t teching hospitls. J Emerg Med. 1999;4: Wre MA, Hmbleton I, Ochy I, et l. Dy-cre mngement of sickle cell pinful crisis in Jmic: model pplicble elsewhere? Brit J Hemtol. 1999;104: Wright J, Breford D, Wright C, et l. Dy cre mngement of sickle pin: 3 yers experience in UK sickle cell unit. Brit J Hemtol. 2004;126: Blls SK, Lusrdi M. Hospitl redmission for dult sickle cell pinful episodes: frequency, etiology nd prognostic significnce. Am J Hemtol. 2005;79: Booker MJ, Blethyn KL, Wright CJ, Greenfield SM. Pin mngement is sickle cell disese. Chronic Illn. 2006;2: Jcob E, Mueller BU. Pin experience of children with sickle cell disese who hd prolonged hospitliztion for cute pinful episodes. Pin Med. 2008;9: n 1032 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 102, NO. 11, NOVEMBER 2010