5 The Canadian Joumal of Hospital Pharmacy - Volume 48, No. 4, August 1995 218 Surveillance of Midazolam Infusions in ICU Ivana A. Macak, Charles D. Bayliff and Gary D. Block
ABSTRACT RESUME In order to determine the utilization of midazolam Une etude retrospective de 17patients mis sous ventilation (MDM) infusions and to assess for the development of assistee et ayant re9u 18 perfusions de midazalam (MDM) tachyphylaxis and withdrawal reactions with MDM, du rant leur sejour aux soins intensifs a ete effectuee pour 17 mechanically-ventilated patients who received 18 que /'on puisse definir /'utilisation des perfusions de courses of MDM infusions during their stay in ICU MDM et evaluer /es conditions de survenue de were studied retrospectively. tachyphylaxie et de reactions de sevrage associees au With a mean age of 52 years (range: 22-78), the MDM. average starting, maintenance and peak infusion rates Les patients etaient ages en moyenne de 52 ans ( ecart de were 1.0 t 0.6, 1.9 t 1.3, and 3.8 t 4.6 mcg/kglmin, 22 a78 ans). Les vitesses de perfusion initiate, de maintien respectively. Patients received the infusion for a mean et maximale etaient de 1,0 t 0,6, de 1,9 t 1,3 et de 3,8 of 9.1 days (range: 0.6-16.1). t 4,6 µg/kg/min, respectivement. Les perfusions ont ete An inverse relationship was found between age and administrees en moyenne durant 9,1 }ours (ecart de 0,6 mean lowest daily Glasgow Coma Scale (GCS) scores al6,l). (r=-0.60, n=l4,p=0.02). lncreases in the mean daily Un rapport inverse a ete observe entre l 'age et !es scores MDM infusion rate, suggestive oftachyphylaxis, were quotidiens moyens les plus faibles (r = 0,60; n = 14; also noted (n=l8, p<0.01 ). Ten patients were studied p = 0, 02) a l 'echelle de «coma» de Glasgow ( GCS ). On a for use of CNS drugs after MDM discontinuation. aussi remarque que des augmentations de la vitesse Three patients who required haloperidol during the 24 moyenne quotidienne de la perfusion de MDM pouvaient hours following MDM discontinuation received larger laisser prevoir la tachyphylaxie (n = 18; p < 0,01). doses of MDM than the remaining seven patients ( 3.6 Dix patients ont ete evalues relativement a I 'utilisation t 1.8 versus 1.2 t 0.6 mcg/kglmin, n=JO, p=0.05). de depresseurs du SNC apres le retrait du MDM. Les trois Concurrent use of diazepam during the 24 hours prior patients qui ont eu besoin d' haloperidol dans les 24 heures to MDM discontinuation was documented in seven of suivant le retrait du MDM avaient re9u de plusfortes doses ten patients. de MDM que les sept autres patients ( 3,6 t 1,8 versus 1,2 The inverse relationship between age and GCS scores to,6 µg/kg/min: n = 10,p = 0,05). L'usageconcomitant is suggestive of decreased clearance or enhanced de diazepam dans les 24 heures precedant le retrait du sensitivity to MDM in older patients. Concurrent use of MDM a ete documente chez sept des dix patients. diazepam, possible. development of tachyphylaxis and Le rapport inverse entre l 'age et /es scores a l 'echelle withdrawal reactions to MDM were also found. These GCS semble indiquer une clairance reduite ou une findings may be useful in developing guidelines for use sensibilite accrue au MDM chez /es patients plus ages. On of MDM infusions. a egalement note un usage concomitant de diazepam, un Key Words: midazolam infusion, tachyphylaxis, risque de tachyphylaxie et des reactions de sevrage associes withdrawal reactions. au MDM. Ces resultats pourraient etre utiles dans /'elaboration de lignes directrices sur /'utilisation des perfusions de MDM. Mots cles : perfusion de midazolam, reactions de Can J Hosp Pharm 199S; 48:218-223 sevrage, tachyphylaxie
INTRODUCTION advantages of MDM infusions over metabolites. 3 Due to the short duration Continuous midazolam (MDM) diazepam include a short duration of of effect, some authors have infusions are sometimes used in the action, avoidance of frequent documented faster recovery and management of agitation and anxiety intravenous (IV) bolus administration, extubation with MDM than with in ventilator-dependent patients in the low incidence of local irritation at the diazepam in coronary artery bypass cirtical care setting. 1•2 Some of the site of injection and the lack of active patients.2
I. Macak, B.Sc. Phm., is a Phannacist, Credit Valley Hospital, Mississauga, Ontario. This project was completed during her Phannacy Residency Program at Victoria Hospital, London, Ontario, and received the 1990-91 CSHP Merck Frosst Award for Rational Drug Use. C. Bayliff, Phann.D., is a Clinical Coordinator of Phannacy Services, Victoria Hospital, London, Ontario. G. Block, M.D. F.R.C.P.(C), is a Critical Care Trauma Centre Consultant, Depanment of Anaesthesia at Victoria Hospital. Acknowledgements: The authors would like to acknowledge Ms. E. Yoshida for herassistanceduring the study, Dr. D. Mills and Dr. M. Spino for their editorial guidance, and Dr. T. Einarson for evaluation of statistical analysis. Address Correspondence to: Ivana A. Macak, B.Sc.Phm., Depanment of Phannacy, Credit Valley Hospital, 2200 Eglinton Ave. W., Mississauga, Ontario L5M 2Nl 219 The Canadian Journal of Hospital Pharmacy - Volume 48, No. 4, aout 1995 1
Unfortunately, there is little analysed retrospectively: demo recording additional doses of CNS T infonnation on dosing of the drug in graphics and primary diagnosis; depressants administered during the critically ill patients and what has dosing, duration and means of 24 hours following discontinuation been published indicates marked inter discontinuation (weaning versus of MDM infusion. The difference in individual variability. 3-5 Furthennore, abrupt discontinuation) of MDM requirements for additional CNS there have been reports in the literature infusions; orders for concurrent and depressants between patients who of prolonged elimination half-life subsequent use of other central were weaned and patients who were (t 1/2) and accumulation of MDM in nervous system (CNS) depressants not weaned off MDM was also mechanically ventilated patients, (i.e., benzodiazepines, narcotics, assessed. Patients were considered to especially those with altered hepatic barbiturates and neuroleptics); daily be 'weaned' if there was at least one function.6-8 serum creatinine, aspartate amino dose reduction in MDM infusion, Like other benzodiazepines, MDM transferase (AST), total bilirubin during the 24 hours prior to discon has been associated with the concentrations and lowest Glasgow tinuation of the infusion. development of tolerance. 9-10 Several coma scale (GCS) scores during cases of withdrawal reactions with MDM infusion; and time to extubation STATISTICAL ANALYSIS MDM have also been reported in the with respect to discontinuation of Linear regression analysis and literature, including convulsions, MDM. Elevations in direct bilirubin calculation of Pearson's correlation anxiety and tachycardia. 11 -13 and prothrombin time (PT), in the coefficient 'r' were used to detennine Finally, since MDM is also more absence of warfarin therapy or the relationships between demo expensive than other benzodiazepines, documented disseminated intra graphic data (i.e'., age and GCS scores) surveillance of the current utilization vascular coagulopathy (DIC), were and mean MDM infusion rates. Linear C. of MDM was undertaken to assist in also recorded. Since neuromuscular regression was also utilized in M the development of guidelines and blocking agents lower GCS scores, evaluating the development of criteria for its use. lowest daily GCS scores were not tachyphylaxis. Epistat Statistical recorded on days patients received Package for IBM personal computer OBJECTIVES either infusions or bolus doses of was used for these statistical T: A retrospective review of MDM pancuronium or vecuronium. calculations. The mean MDM infusions administered to patients in Due to the potential effects of renal/ infusion rate in patients who required the Intensive Care Unit (ICU) was hepatic impairment on MDM dosing haloperidol following MDM dis conducted with the following requirements, patients with such continuation versus those who did objectives: condition(s) were identified according not was assessed by Mann-Whitney 1) To detennine the utilization of to the following definitions: renal U test (one-way). Fisher's Exact test MDM with respect to dose, dysfunction was defined as calculated was used to compare the proportion duration of therapy and patient creatinine clearance (CrCl, Cockcroft of weaned patients versus those not demographics and to assess & Gault formula) equal to or below weaned, who required additional CNS relationships between certain 0.33 mL/sec on two consecutive depressants following MDM dis demographics, such as age and measurements during MDM infusion continuation. MDM dose requirements. or the need for dialysis. Patients were 2) To detennine if tachyphylaxis considered to have hepatic dys RESULTS occursinpatientsreceivingMDM function if they fulfilled two or more Utilization and Dose/Demographic infusions. of the following criteria: elevated AST Relationships 3) To monitor for withdrawal (>40U/L), elevated total bilirubin Seventeen patients received a total of reactions to MDM and to assess (> 17 umol/L) in the absence of blood 18 treatment courses of MDM whether the occurrence of these transfusions or hemolysis, elevated infusions during the study period. All can be influenced by the means direct bilirubin (> 10 umol/L) and patients were ventilator-dependent at of discontinuing the drug (i.e., elevated PT (> 12 sec) in the absence the start ofMDM infusion. One patient weaning). of warfarin therapy or documented (#10) received MDM infusion twice, DIC. six days apart. She was not extubated * METHODS Tachyphylaxis was assessed by during that time. (Table I) :r,, All patients administered MDM relating mean daily MDM infusion The mean age was 52 ~ 18 years infusions in the ICU during a five rates (per kg of body weight) with (range: 22-78). Four patients expired *l week study period were included in respect to time (days of MDM while on MDM and two patients re, the study. The following infonnation infusion). The occurrence of with (#12,17) died subsequent to MDM ex was collected for all the patients and drawal reactions was measured by discontinuation. Time to extubation in, The Canadian Journal of Hospital Pharmacy - Volume 48, No. 4, August 1995 220
Table I: Patient Demographics and Primary Diagnosis was documented for the remaining 11 patients. Renal (R) Patient Age Gender Condition or Hepatic (H) Outcome MDM was prepared in a 5% (years) Number Dysfunction dextrose or normal saline solution at a concentration of 0.5-2 mg/rnL. The 1. 35 M multiple trauma starting, mean ( excluding weaning 2. 56 F inferior MI 3. 60 M postop. bowel infarction R+H expired rates) and peak infusion rates for each 4. 58 M respiratory failure, asthma patient are summarized in Table II. 5. 51 M infected carotid endarterectomy As a result of concurrent use of 6. 28 M multiple trauma neuromuscular blockers, 42 patient 7. 23 M intraabdominal sepsis days of GCS data (25.5%) were 8. 78 M acute bowel obstruction expired 9. 42 M sacroiliac abscess, sepsis expired excluded from a total of 164.5 days IO.A 61 F anteroseptal MI studied. 10.B 61 F anteroseptal MI expired There were no statistically signifi 11. 75 F mitral valve repair cant relationships between age and 12. 69 M cardiac failure post MI H expired mean MDM infusion rate (r=-0.25, 13. 22 M multiple trauma 14. 34 M toxic shock R n=18, p=0.31) nor between mean 15. 62 M double CABG MDM infusion rate and the mean 16. 41 M anoxia to brain due to hanging lowest daily GCS scores (r=-0.24, 17. 73 M postop. retroperitoneal bleed R+H expired n=18, p=0.33). However, an inverse
CABG Coronary Artery Bypass Graft relationship was found between age MI Myocardial Infarction and the mean lowest daily GCS scores (r=-0.63, n=l8, p=0.005). Upon excluding the four patients with hepatic and/or renal impairement, the Table II: Midazolam Infusion Data correlation coefficient between age and MDM Patient Initial Mean Peak Mean Duration Meansof Timeto infusion rate improved but Number Infusion Infusion Infusion Lowest of Midazolam Extubation was still not statistically Rate Rate Daily Infusion Discontinuation hours Rate significant (r=-0.37, n= 14, meg/kg meg/kg meg/kg Glasgow days per min - permin per min Coma p=0.19). The correlation Score between age and GSC scores persisted in this patient group I.ob 0.49 0.32 0.59 9.8 14.8 w -21 (r=-0.60), n=14, p=0.02). 2. 1.60 1.67 2.56 9.0 7.0 NW 72 ***3.nb 0.91 1.97 4.54 6.9 9.2 - - 4. 0.71 2.11 2.38 10.0 1.9 NW 3 Tachyphylaxis 5. 1.09 1.09 1.09 11.3 12.2 w -24 For all but four patients 6.nb 2.32 4.68 6.48 7.2 12.9 NW 4 (#5,9,11,16) there was an 7.nb 1.09 4.65 21.79 9.0 15.9 NW 48 increase in MDM infusion 8.nb 0.43 0.53 1.07 4.2 10.9 - - 9.nb 0.42 0.42 0.42 9.7 12.7 - - rate with time, with day zero IO.A 1.25 3.22 4.17 7.8 6.2 NW - (i.e., the initial infusion rate, 10.B 0.83 2.64 5.21 6.3 13.2 - - n= 18) being significantly II. 0.62 0.62 0.62 7.7 2.1 w 100 lower than day ten (r=0.92, **12.nb 0.47 1.02 2.34 7.8 9.2 NW - n=lO, p<0.01). (Figure 1) 13.nb 1.12 1.29 2.23 12.8 16.1 w 260 *14.nb 0.33 1.55 1.67 8.0 9.3 w 130 15. 1.00 1.70 2.00 8.0 2.3 w 44 Withdrawal 16. 1.11 1.11 1.11 9.5 0.6 NW 2 Seven patients were weaned ***17.nb 2.56 3.32 7.76 4.8 8.0 w - off MDM infusion, while MEAN: 1.0 1.9 3.8 8.3 9.1 74 seven patients had MDM SD: 0.6 1.3 5.0 2.1 5.0 abruptly discontinued. Weaning was usually done */**=renal/hepatic dysfunction, respectively;***= renal and hepatic dysfunction; nb = patient by 1 to 2 mL (i.e., 0.5-4 mg) received neuromuscular blocker during midazolam infusion; W = weaned; NW = not weaned; Time to extubation is measured from the time of midazolam infusion discontinuation, where a negative number hourly decrements in indicates the patient was extubated prior to discontinuation of midazolam. infusion rate, over 4 to 19 221 The Canadian Journal of Hospital Phannacy - Volume 48, No. 4, aout 1995 The Ca hours. Data on doses of other CNS patients received haloperidol during every 10 to 15 minutes as needed) at co lie: depressants administered concurrently the 24 hours following MDM some point during MDM infusion, elimir (i.e., 24 hours prior to) and subsequently discontinuation. The mean MDM seven of the ten aforementioned males (i.e., 24 hours after discontinuation of infusion rate was greater in these patients received doses of diazepam to tha1 MDM infusion) were collected on ten patients (3.6 ~ 1.8 mcg/kg/min) than (5-55mg) during the 24 hours prior to aged: patients. (Table III) in patients who did not receive MDM discontinuation. Five of these autho Eight of the ten patients received haloperidol (1.2 ~ 0.6 mcg/kg/min, seven patients still received doses of reduc additional doses of CNS depressants n=7; Mann-Whitney U test, one diazepam during the 24 hours elder) in the first 24 hours following MDM tailed: p=0.05). following MDM discontinuation. Greer discontinuation-two of four 'weaned' While all seventeen patients were great< patients and six of six patients in prescribed diazepam (2.5-5 mg IV OISCUSSION plasrr whom MDM was abruptly discon every 15 minutes as necessary for A number oflimitations and difficult 60 ye tinued (Fisher's Exact: p=0.13 ). Three agitation), and morphine (2-5 mg IV to-control variables would exist in 40 y, any study of dose/demographic effec· relationships, tachyphylaxis and statis 2 7 withdrawal reactions to benzodi two 10 ~ : Imcg/kg/min I azepines in the critical care setting. intrir 2.25 Varying need for pain control among patie 2 ,. patients, subjective determination of In optimal sedation by attending nurses signi 1.75 and medical staff, concurrent use of foum 1.5 muscle relaxants, previous use of Mrn 1.25 benzodiazepines by the patient prior four to hospital admission, increased dysfi agitation due to increasing recovery Exel .75 ,. of consciousness or increased stress addi . 5 ,. secondary to weaning patients off orre . 25 , . mechanical ventilation, withdrawal com reactions to narcotics and the mea 0 0 .5 2 3 4 5 6 7 8 9 10 occurrence oflCU psychosis are only n=ll Days of Midazolam Infusion * no. of patients some of these variables. The control may of such variables was beyond the scope rela1 Figure I: Mean Daily Midazolam Infusion Rate of this retrospective review. However, dost some trends and observations can be pati1 useful in developing guidelines for tical Table III: Additional Doses of Other CNS Depressants Administered During the 24 MDM use in ICU - an area where Con Hours Following Midazolam Infusion Discontinuation (Numbers indicate few such guidelines are currently in how many more milligrams of each drug were given during the 24 hours the following discontinuation of midazolam infusion compared to doses existence. diff1 administered during the 24 hours prior to midazolam infusion discontinuation.) to ti Utilization and Dose/Demographic MC Patient Diazepam Haloperidol Lorazepam Morphine Relationships typ< Number IV (mg) IV/IM (mg) SL/PO mg IV (mg) Seventeen critically ill patients who r- Patients Weaned received 18 courses ofMD M infusions M[ I. were studied. The MDM infusion rates GC 5. used in these patients were compar wh1 13. 25 able to those reported by others in difJ 14. 10 33 the literature, ranging from 0.5 to CN I,3,5,I0,11,14,15 Patients not Weaned 6 mcg/kg/min. Also, as use 2. 12.5 noted by others, the dose requirements inv 4. 5 1 varied markedly among different me 6. 25 patients. 5•8•16 not 7. 115 54 121 Decreased total clearance ofMDM cot 12. 52 in older males but not females has dee 16. 6 been documented. 17•18 Greenblatt and ser ~5 The Canadian Journal of Hospital Pharmacy - Volume 48, No. 4, August 1995 222
at colleagues reported prolonged described by Greenblatt et aI. 17,19 tered during the 24 hours following n, elimination half-life of 5.6 hours in However, since serum MDM concen MDM discontinuation were recorded :d males, aged 60 to 74 years, compared trations were not measured, one cannot in this study. Ideally, a control group m to that of2. l hours in younger males, determine whether accumulation of similar in all aspects to the MDM to aged 24 to 33 years. As a result, the this drug occurred in elderly patients. group would be needed to assess the ,e authors recommended a 25 to 50% Furthermore, the lower CGS scores issue of additional CNS medications. )f reduction in MDM infusion rates in in older patients could also represent Because of the logistical problem of rs elderly males. 17 In another study by poorer neurological status due to age, identifying and adequately matching Greenblatt et al, the authors found underlying condition, or impaired the groups, the cited number of CNS greater EEG changes at any dose or clearance of other drug therapies. medications was chosen (Table III). plasma level ofMDM in patients over The number of patients was too small, t 60 years compared to patients under Tachyphylaxis however, (n=l0) to assess for in 40 years of age. The MDM median Figure 1 depicts mean daily MDM differences in doses of additional CNS ic effective concentrations (ECso) were infusion rates for all patients, from depressants administered following 1d statistically different between these the start of the infusion (n= 18) and up the discontinuation ofMDM infusion l two groups, indicating increased to ten days thereafter (n= 10). There in weaned versus not weaned patients. g. intrinsic sensitivity to MDM in older was a statistically significant doubling Of note, the three patients who were tg patients. 19 of the mean MDM infusion rate by prescribed haloperidol received larger )f In this study, no statistically the seventh day of infusion (n= 14, doses of MDM than the other seven ~s significant linear relationships were p<0.0 I). While this may constitute patients (Mann-Whitney U Test, )f found between age and patient's mean tachyphylaxis, serum MDM concen one-tailed, n=lO, p=0.05). As with )f MDM infusion rate, even when the trations would be needed to confirm other benzodiazepines, the risk of )r four patients with hepatic and/or renal these findings. withdrawal reactions increases with :d dysfunction were excluded (r=-0.37). Meyer et al have briefly reported higher doses. It would, therefore, :y Exclusion of female patients in on the occurrence of tachyphylaxis seem prudent to wean MDM in ,s addition to patients with hepatic and/ with MDM in a study of 18 pediatric such patients. 13 Unfortunately, in this ff or renal impairment, yielded a higher ICU patients on ventilators. Patients study, theinfluenceofweaningMDM al correlation coefficient for age and receiving the infusion beyond 72 hours infusion on the occurrence of with 1e mean MDM infusion rate (r=-0.46, required higher doses of MDM. drawal reactions was not statistically ly n= 10, p=0.18). While these findings However, the authors did not mention detectable. JI may be suggestive of an inverse the statistical significance of their The final finding was that diazepam Je relationship between age and MDM findings. 10 Shelly and colleagues was administered concurrently to ,r, dose requirements, especially in male noted significant increases in MDM patients on MDM infusions. Seven of ,e patients, they have not been statis dose in adult ICU patients on the ten patients received doses of )r tically substantiated in this study. continuous MDM infusions.20 It diazepam during the 24 hours prior to re Consideration should also be given to would appear, then, that the potential stopping MDM infusion. The redun in the intentional and unintentional for tachyphylaxis with MDM exists. dance of the double benzodiazepine differences in dose-titration endpoints therapy, with potential loss of the to the sedative or hypnotic effects of Withdrawal anticipated short-term effects of ic MDM, which could largely affect this Withdrawal reactions are more MDM is of serious concern. An type of a relationship. commonly seen with shorter acting inclusion of a cautionary statement lO No relationship was found between drugs than with longer acting agents. regarding this issue should be given lS MDM dosing and mean daily lowest MDM, one of the shortest-acting consideration in the development of ~s GCS scores. This is not surprising benzodiazepines available today, dosing guidelines for MDM infusions. ~ r when one considers the potential would be expected to produce similar in differences in the desired level of effect. 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