Resuscitation 85 (2014) 533–537
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Heparin dosing in critically ill patients undergoing therapeutic hypothermia following cardiac arrest夽 Krista A. Wahby a,∗ , Sunil Jhajhria b , Bhavinkumar D. Dalal b , Ayman O. Soubani b a
Critical Care, Harper University Hospital, Detroit Medical Center, Wayne State University, United States Division of Pulmonary and Critical Care Medicine, Wayne State University, School of Medicine, Harper University Hospital, Detroit Receiving Hospital, Detroit Medical Center, 3990 John R., Detroit, MI 48201, United States b
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 15 November 2013 Accepted 6 December 2013 Keywords: Heparin Anticoagulant drugs Hypothermia Cardiopulmonary arrest Dose–response relationship Drug
a b s t r a c t Purpose: To determine the effects of anticoagulation with intravenous unfractionated heparin (IVUH) during therapeutic hypothermia (TH) post-cardiac arrest. Methods: Single-center, retrospective, observational trial in the intensive care units of two hospitals within the Detroit Medical Center. Unresponsive survivors of cardiac arrest, receiving treatment doses of IVUH during TH were included. Patients were required to have at least 1 measured activated partial thromboplastin time (aPTT) during TH. Coagulation parameters were collected at 3 distinct temperature phases: baseline, TH, and post-re-warming (±37 ◦ C) target aPTT defined as 1.5–2 times baseline. Results: Forty-six patients received IVUH during TH, with 211 aPTTs. Heparin starting rate was 13 ± 4 units/kg/h. Average baseline, TH and post-TH aPTT were 34 ± 12, 142 ± 48, and 56 ± 17 s, respectively. Using standard dosing strategies, initial aPTT was above the target range in 89% of patients. After re-warming, aPTT significantly decreased (142 ± 48 s vs 56 ± 17 s, p = 0.005), and heparin dose significantly increased (7.9 ± 3 vs 9 ± 4 units/kg/h, p < 0.001). There was a significant difference between aPTT among all three groups, and heparin dose between TH and post-TH even after correcting for age, sex, body mass index, heparin rate, and APACHE II score (p < 0.001). Three patients experienced a major bleeding event. Conclusions: Current dosing protocols for IVUH should not be utilized during TH. Heparin requirements are drastically reduced during TH and prolonged interruptions may be required to allow for adequate clearance of UH. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Survivors of sudden cardiac death have improved neurological outcomes and survival when treated with mild therapeutic hypothermia (TH).1,2 Growing evidence supports TH for a variety of other conditions including, but not limited to asphyxial arrest in neonates, stroke and interventional cardiology.3 Therapeutic hypothermia is endorsed as the standard of post-resuscitation care by the International Liaison Committee on Resuscitation (ILCOR) and the American Heart Association.4,5 When the etiology of sudden cardiopulmonary arrest is unknown, the differential includes thromboembolic events, including acute myocardial infarction and pulmonary embolism. These
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.12.014. ∗ Corresponding author at: 3990 John R., Harper University Hospital, Detroit, MI 48201, United States. E-mail address: [email protected] (K.A. Wahby). 0300-9572/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.resuscitation.2013.12.014
conditions are usually treated with systemic anticoagulation. In the intensive care unit, intravenous unfractionated heparin (IVUH) is often preferred due to its favorable pharmacodynamic profile in the critically ill and ease of reversibility. While the period of TH is often short (12–24 h), the pharmacokinetics of many commonly used medications are unknown, predisposing patients to undesirable adverse drug reactions or altered drug disposition.6–8 The pharmacokinetic profile of IVUH during TH is not well understood, and dosing inadequacy may result in therapeutic failure or increased bleeding risk. We hypothesized that patients undergoing TH who receive IVUH for systemic anticoagulation experience altered heparin metabolism resulting in supratherapeutic activated partial thromboplastin times (aPTT). The primary aim of this study was to assess the efficacy of our current IVUH dosing protocol in achieving therapeutic aPTT values during TH. In addition, we studied the frequency and range of IVUH dosing during and after TH. To date, this is the first published study which has evaluated IVUH dosing requirements during TH, post-cardiac arrest.
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K.A. Wahby et al. / Resuscitation 85 (2014) 533–537
2. Methods
2.3. Monitoring for bleeding
The study was performed at Harper University Hospital and Detroit Receiving Hospital, Detroit, MI which are university based academic hospitals; part of the Detroit Medical Center (DMC). The study was conducted over a 6 year time frame, September 2006 through August 2012. Patients were included if on TH in the intensive care units (ICU) at either of the hospitals and received IVUH. The study was approved by the Wayne State University, Human Investigation Committee and by the DMC Research Review Committee. Informed consent was not required for this study. Hypothermia was implemented using the Arctic Sun Temperature Management System® (Medvance Inc., Covington, GA). This system utilizes external cooling techniques to achieve TH in unresponsive survivors of cardiac arrest. The protocol for TH at the DMC involves rapid external cooling to a target core body temperature of 33 ◦ C, monitored through an esophageal probe. The TH temperature of 33 ◦ C is maintained for 24 h, followed by a slow re-warming phase (0.5◦ C/h until 37 ◦ C). At this point, patients remain on the TH machine, fixed at a temperature of 37 ◦ C for 48 h, or until patient shows signs of responsiveness. Our protocol is initiated in nonresponsive survivors of cardiac arrest after they are intubated and on controlled ventilation. Serum electrolytes, glucose, blood cultures, amylase and lipase are monitored closely.
We screened all patients for bleeding events. Bleeding is assessed at least once daily for all patients by the anticoagulation service, and major and minor bleeding events are recorded. In addition, the principle investigator rounds in the ICU daily Monday through Friday and assesses bleeding during therapy. Major bleeding was defined as a drop in hemoglobin of greater than 2 g/dl in 24 h, requiring transfusion on 2 consecutive days, or any major bleed as perceived by the intensivist caring for the patient.
2.1. Study design and data collection Using a retrospective cohort study design, patients with concomitant orders for both TH and IVUH were identified through the pharmacy database (Med Manager, Cerner, Inc.). Patients in the ICU, on TH were monitored closely by the heparin dosing service. The following baseline variables were recorded: age, gender, height, actual body weight (ABW), body mass index (BMI), ideal body weight (IBW), adjusted body weight (AjBW), the acute physiology and chronic health evaluation (APACHE) II score at the time of heparin initiation, indication for UH, initial heparin dose in units/kg/h, and baseline coagulation tests (aPTT, prothrombin time (PT) and international normalized ratio (INR). 2.2. Heparin dosing and coagulation testing All patients were required to have at least 6 h of IVUH and one corresponding aPTT drawn during TH to be included in the analysis. Data was grouped into three distinct temperature ranges: baseline (pre-hypothermia), TH (up to 3 aPTT readings drawn while core body temperature was 33 ◦ C), and post-re-warming (≥37◦ C). All coagulation testing was performed by the Detroit Medical Center’s Core Hematology STAT lab, and samples were sent in blue-top tubes for analysis. The DMC uses the fully automated, Sysmex® CA 1500 coagulation system for aPTT analysis. The majority of aPTT results are reported in the ICU within 30–45 min. The upper aPTT limit for reporting is 200 s. For the purposes of statistical analysis, all measurements reported as >200 s were rounded to 200 s. Anticoagulation therapy is managed by the DMC pharmacy department and adjustments to IVUH rates were performed by a 24-h pharmacy dosing service according to established dosing nomograms.9 All dose adjustments, including interruptions in the IVUH infusion were recorded and reported. The DMC utilizes a comprehensive electronic medical record, with electronic physician order entry, and barcode scanning for medication administration. Heparin dosing requirements were documented as units/kg/h based on total body weight, unless the body mass index was >30 m2 . In these cases, an adjusted body weight ([actual weight − ideal body weight][0.4] + IBW) was used for dosing. Therapeutic aPTT was defined as aPTT of 1.5–2 times baseline aPTT (s).
2.4. Statistical analysis Continuous variables were expressed as mean ± standard deviation for normally distributed variables. Chi-square or Fisher’s exact test were used to compare categorical variables, as appropriate. For purposes of analysis, the temperature readings with corresponding aPTT and heparin rates were grouped into three distinct subsets: baseline, TH and post-re-warming. Descriptive statistics were performed on aPTT and heparin rates during the 3 temperature points. A Bartlett’s test was performed to test for equal variances between groups. An ANOVA test was performed to test for significance of heparin dose and aPTT among the 3 groups and a Bonferroni post hoc analysis was performed to identify differences between groups. A multinomial logistic regression analysis was performed to test for PTT differences between the three phases. The variables of age, sex, BMI, heparin rate and APACHE score were tested for significance between groups. The p-values were calculated using a two-sided analysis, and the level of significance was set at 200 s, and the other patient had two consecutive readings of >100 s. In all cases, heparin was discontinued. 4. Discussion The safety of systemic anticoagulation therapy during TH is an area of controversy. Coagulopathy itself is often viewed as a relative contraindication for TH. However, in cases of sudden cardiac death associated with thrombotic events, including pulmonary embolism and acute myocardial infarction, systemic anticoagulation remains the mainstay of therapy. Under normal conditions, heparin is bound to antithrombin, which ultimately causes inactivation of thrombinmediated conversion of fibrinogen to fibrin.10 Intravenously UH has a relatively short half-life and can be reversed with protamine, offering it some advantages in critically ill patients. Heparin’s clearance is saturable and may be highly effected by temperature.10 In
K.A. Wahby et al. / Resuscitation 85 (2014) 533–537
aPTT (seconds)
aPTT
Heparin Rate
160
16
140
14
120
12
100
10
80
8
60
*Target aPTT range
6
40
4
20
2
0
Heparin Rate (Units/kg/hr)
536
0 Baseline
TH
Post Re-warming
aPTT: activated partial thromboplastin time; TH: therapeutic hypothermia; kg: kilograms; hr: hour *The Detroit Medical Center's anticoagulation protocol typically targets aPTT=48 to 78 seconds
Fig. 2. Heparin rate and response.
addition, since the clotting cascade depends on multiple enzymatic processes leading to thrombin production, the entire cascade may be altered under hypothermic conditions.11 This mechanism would explain the elevated aPTTs and prolonged periods of interruption before aPTT fell to a normal treatment range. Therapeutic hypothermia gained worldwide support after two landmark studies were published in the New England Journal of Medicine in February 2002.1,2 In the major trial of 275 patients with cardiac arrest, TH improved neurological outcome when patients were cooled to 32–34 ◦ C for 24 h.1 In this study 55% of the patients in the hypothermia group had favorable neurologic outcome at 6 months, compared to 39% in the normothermia group (risk ratio, 1.40 (CI 1.08–1.81). Mortality was also significantly less in the hypothermia group, 41% vs 55%, p = 0.02, RR, 0.74 (CI 0.58–0.95). Bleeding rates through day 7 were 26% and 19% in the TH and normothermia groups, respectively, however, coagulation testing and anticoagulant medications were not described. In the other trial by Bernard et al., cooling was induced quicker, but sustained for only 12 h which may limit the pharmacodynamic and pharmacokinetic alterations.2 In our study, all patients were on IVUH and most exhibited a dramatic response to IVUH expressed as aPTT elevations, and prolonged periods of interruption in the UH infusion before the aPTT fell back into a target range. 250
Heparin Dose (Units/kg/hr)
aPTT (seconds)
200
In our study, only 3 patients achieved aPTT in the target range after initial dosing, and the dose of IVUH in these three patients was lower than standard dosing protocols, suggesting that over time, increased awareness of our findings led to more conservative dosing strategies. It is important to point out that we had 5 patients in our study who were already fully anticoagulated with heparin prior to cardiac arrest. These patients served as their own control, and all 5 patients showed significant elevations in aPTT despite pre-TH values that were all in the target range. Our hospital performs quarterly quality analysis of 100 randomly selected patients, managed by the heparin dosing service. Upon review of our 2012 data, 68% of patients achieved aPTTs in the target range at 24 h, 22% were below and 10% were above, and very rarely were aPTTs > 200 s. In our subset of patients, at 24 h into the TH protocol, 10 (22%) patients achieved target aPTT, which emphasizes the challenges that we face with current heparin dosing protocols during TH. Other pharmacokinetic and pharmacodynamic parameters may be significantly altered during TH, specifically, reduced drug clearance.6–8 Limited data suggests altered pharmacokinetic profiles for some of the commonly used ICU medications including fentanyl, morphine, benzodiazepines, and the neuromuscular blocking agents.6–8 Bjelland et al. proved that the clearance of morphine, fentanyl and propofol were all significantly lower during TH.7
150
100
50
20 15 10 5 0
0 Baseline
TH Fig. 3. aPTT results.
Post Re-warming
Baseline
TH
Post Re-warming
Fig. 4. Heparin dosing requirements.
K.A. Wahby et al. / Resuscitation 85 (2014) 533–537
Cohen et al. studied plasma heparin levels in patients undergoing cardiopulmonary bypass and showed that mean heparin plateau levels increased during hypothermia with each heparin bolus administered.12 Insignificant decay was cited as the rationale. Once re-warmed, heparin levels declined linearly, at a rate proportional to the starting heparin level. In our study, heparin rates increased significantly after re-warming in order to achieve, or maintain the target level of anticoagulation, a similar finding to the Cohen study. The only other published study assessing anticoagulation with heparin in patients on mild TH post-cardiac arrest was performed by Spiel et al.13 They assessed 18 patients on TH, induced by cold IV fluids, and receiving therapeutic anticoagulation with either IVUH (n = 16) or enoxaparin (n = 2). They reported a 2.7-fold increase in aPTT from baseline. The aPTT did not return to normal until 24 h after TH was complete. The graphic display of aPTTs in this study shows aPTT 1 h after TH was approximately 140 s, similar to our findings. This suggests a rapid effect of TH on heparin pharmacodynamics. No bleeding events were recorded in this study, a significant finding considering that many clinicians would question application of TH in patients fully anticoagulated prior to cardiac arrest. The study did not report heparin rates or dosing strategies. The small sample size in this study may have failed to detect significant bleeding events. Whether TH alone increases bleeding risk remains controversial. Prolongation of bleeding times and reduced thromboxane concentrations have been seen during TH.14 However, in a recent meta-analysis, bleeding was not significantly different between the cooled patients and normothermic patients.15 We assessed a random cohort of our critically ill patients, on the same TH protocol, during the study period and found no significant increase in aPTT from subcutaneous heparin for VTE prophylaxis. Patients in both groups had similar APACHE II scores. It is important to point out our study limitations. While this is the first study to look at IVUH dosing in TH, we have adjusted dosing strategies in some patients over time due to increased awareness of the elevated aPTT phenomenon. Thus, not all patients were dosed according to strict protocol guidelines. All patients, however, were followed by our pharmacy anticoagulation team and by clinical pharmacy specialists who round daily in the ICU with a multidisciplinary team and inquire daily about bleeding events, etc. While retrospective in nature, patient profiles are saved and bleeding events are noted on our monitoring sheets. Secondly, the lack of plasma heparin concentrations to correlate our findings with the pharmacokinetics of heparin is a significant limitation. We suspect that heparin metabolism and clearance are both reduced, but without drug levels, we are unable to prove this. The sensitivity of the aPTT testing must be acknowledged. Since the upper limit for the machine is 200 s, for the purpose of our statistical analysis, these were rounded to 200 s. This may falsely lower the true rise in aPTT. Therefore, the change in aPTT from baseline may actually be higher than our estimates. Finally, the best test for monitoring anticoagulation during TH is not clear. It is possible that thrombin time, heparin levels, or activated clotting time may be more predictable tests during TH, but this is not the standard of care for monitoring heparin in most hospitals in the United States. Our institution has since created a modified heparin dosing protocol (40 units IV bolus, followed by 7 units/kg/h) for use during TH. Data collection to validate the effectiveness of this protocol is ongoing. 5. Conclusion The beneficial effects of TH are substantial, and include neuroprotection mediated by a reduction in cerebral metabolism of glucose and oxygen, reduced cerebral edema, decreased
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thrombotic risk, and electrical stabilization of the brain.6 These beneficial effects must be weighed with the knowledge that TH also exerts physiologic alterations throughout the body. More and more data is available which supports dosage reductions for commonly used medications in the critically ill during TH. Lacking to this body of evidence is dosing recommendations for IVUH, a drug with a narrow therapeutic range and risk for toxicity in these patients. This study highlights a concerning issue in the care of critically ill patients undergoing therapeutic hypothermia and provides evidence that dosing recommendations for heparin during TH need to be modified to account for reduced drug clearance. Our study would support a modified dosing protocol for IVUH during TH, with careful monitoring and adjustment of heparin rates during and immediately after TH. Funding source No funding was provided for this study. Conflict of interest statement The authors of this manuscript have nothing to disclose. Acknowledgments The authors would like to acknowledge Dr. Haithem A. ElHaddad for his help with data collection, and the DMC Pharmacy Anticoagulation Service for their outstanding assistance with monitoring these patients. References 1. Holzer M, Cerchiari E, Mertens P, et al. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. 2. Bernard A, Gray TW, Buist MB, et al. Treatment of comatose survivors of out of hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 3. Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1. Indications and evidence. Intensive Care Med 2004;30:556–75. 4. Nolan JP, Morley PT, Vanden Hoeck TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the advanced life support task force of the international liaison committee on resuscitation. Circulation 2003;108:118–21. 5. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: Post cardiac-arrest care: 2010 American Heart Association guidelines for cardiopulmonary arrest and emergency cardiovascular care. Circulation 2010;122:S768–86. 6. Van den Broek MPH, Groenendaal F, Egberts ACG, Rademaker CMA. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 2010;49: 277–94. 7. Bjelland TW, Klepstad P, Haugen B, Nilsen T, Dale O. Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Drug Metab Dispos 2012 [Epub ahead of print; October 13]. 8. Fukuoka N, Aibiki M, Tsukamoto T, et al. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic hypothermia. Resuscitation 2004;60:225–30. 9. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a standard care nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874–81. 10. Reed RL, Bracey AW, Hudson JD, et al. Hypothermia and blood coagulation: dissociation between enzyme activity and clotting factor levels. Circ Shock 1990;32:141–52. 11. Rohrer M, Natale A. Effect of hypothermia on the coagulation cascade. Crit Care Med 1992;20:1402–5. 12. Cohen JA, Frederickson EL, Kaplan JA. Plasma heparin activity and antagonism during cardiopulmonary bypass with hypothermia. Anesth Analg 1977;56:564–9. 13. Spiel AO, Kliegel A, Janata A, et al. Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids. Resuscitation 2009;80:762–5. 14. Valeri RC, MacGregor H, Cassidy G, et al. Effects of temperature on bleeding time and clotting time in normal male volunteers. Crit Care Med 1995;23:698–704. 15. Xiao G, Guo Q, Shu M, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and metaanalysis. Emerg Med J 2013;30:91–100.
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Heparin dosing in critically ill patients undergoing therapeutic hypothermia following cardiac arrest夽 Krista A. Wahby a,∗ , Sunil Jhajhria b , Bhavinkumar D. Dalal b , Ayman O. Soubani b a
Critical Care, Harper University Hospital, Detroit Medical Center, Wayne State University, United States Division of Pulmonary and Critical Care Medicine, Wayne State University, School of Medicine, Harper University Hospital, Detroit Receiving Hospital, Detroit Medical Center, 3990 John R., Detroit, MI 48201, United States b
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 15 November 2013 Accepted 6 December 2013 Keywords: Heparin Anticoagulant drugs Hypothermia Cardiopulmonary arrest Dose–response relationship Drug
a b s t r a c t Purpose: To determine the effects of anticoagulation with intravenous unfractionated heparin (IVUH) during therapeutic hypothermia (TH) post-cardiac arrest. Methods: Single-center, retrospective, observational trial in the intensive care units of two hospitals within the Detroit Medical Center. Unresponsive survivors of cardiac arrest, receiving treatment doses of IVUH during TH were included. Patients were required to have at least 1 measured activated partial thromboplastin time (aPTT) during TH. Coagulation parameters were collected at 3 distinct temperature phases: baseline, TH, and post-re-warming (±37 ◦ C) target aPTT defined as 1.5–2 times baseline. Results: Forty-six patients received IVUH during TH, with 211 aPTTs. Heparin starting rate was 13 ± 4 units/kg/h. Average baseline, TH and post-TH aPTT were 34 ± 12, 142 ± 48, and 56 ± 17 s, respectively. Using standard dosing strategies, initial aPTT was above the target range in 89% of patients. After re-warming, aPTT significantly decreased (142 ± 48 s vs 56 ± 17 s, p = 0.005), and heparin dose significantly increased (7.9 ± 3 vs 9 ± 4 units/kg/h, p < 0.001). There was a significant difference between aPTT among all three groups, and heparin dose between TH and post-TH even after correcting for age, sex, body mass index, heparin rate, and APACHE II score (p < 0.001). Three patients experienced a major bleeding event. Conclusions: Current dosing protocols for IVUH should not be utilized during TH. Heparin requirements are drastically reduced during TH and prolonged interruptions may be required to allow for adequate clearance of UH. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Survivors of sudden cardiac death have improved neurological outcomes and survival when treated with mild therapeutic hypothermia (TH).1,2 Growing evidence supports TH for a variety of other conditions including, but not limited to asphyxial arrest in neonates, stroke and interventional cardiology.3 Therapeutic hypothermia is endorsed as the standard of post-resuscitation care by the International Liaison Committee on Resuscitation (ILCOR) and the American Heart Association.4,5 When the etiology of sudden cardiopulmonary arrest is unknown, the differential includes thromboembolic events, including acute myocardial infarction and pulmonary embolism. These
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.12.014. ∗ Corresponding author at: 3990 John R., Harper University Hospital, Detroit, MI 48201, United States. E-mail address: [email protected] (K.A. Wahby). 0300-9572/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.resuscitation.2013.12.014
conditions are usually treated with systemic anticoagulation. In the intensive care unit, intravenous unfractionated heparin (IVUH) is often preferred due to its favorable pharmacodynamic profile in the critically ill and ease of reversibility. While the period of TH is often short (12–24 h), the pharmacokinetics of many commonly used medications are unknown, predisposing patients to undesirable adverse drug reactions or altered drug disposition.6–8 The pharmacokinetic profile of IVUH during TH is not well understood, and dosing inadequacy may result in therapeutic failure or increased bleeding risk. We hypothesized that patients undergoing TH who receive IVUH for systemic anticoagulation experience altered heparin metabolism resulting in supratherapeutic activated partial thromboplastin times (aPTT). The primary aim of this study was to assess the efficacy of our current IVUH dosing protocol in achieving therapeutic aPTT values during TH. In addition, we studied the frequency and range of IVUH dosing during and after TH. To date, this is the first published study which has evaluated IVUH dosing requirements during TH, post-cardiac arrest.
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K.A. Wahby et al. / Resuscitation 85 (2014) 533–537
2. Methods
2.3. Monitoring for bleeding
The study was performed at Harper University Hospital and Detroit Receiving Hospital, Detroit, MI which are university based academic hospitals; part of the Detroit Medical Center (DMC). The study was conducted over a 6 year time frame, September 2006 through August 2012. Patients were included if on TH in the intensive care units (ICU) at either of the hospitals and received IVUH. The study was approved by the Wayne State University, Human Investigation Committee and by the DMC Research Review Committee. Informed consent was not required for this study. Hypothermia was implemented using the Arctic Sun Temperature Management System® (Medvance Inc., Covington, GA). This system utilizes external cooling techniques to achieve TH in unresponsive survivors of cardiac arrest. The protocol for TH at the DMC involves rapid external cooling to a target core body temperature of 33 ◦ C, monitored through an esophageal probe. The TH temperature of 33 ◦ C is maintained for 24 h, followed by a slow re-warming phase (0.5◦ C/h until 37 ◦ C). At this point, patients remain on the TH machine, fixed at a temperature of 37 ◦ C for 48 h, or until patient shows signs of responsiveness. Our protocol is initiated in nonresponsive survivors of cardiac arrest after they are intubated and on controlled ventilation. Serum electrolytes, glucose, blood cultures, amylase and lipase are monitored closely.
We screened all patients for bleeding events. Bleeding is assessed at least once daily for all patients by the anticoagulation service, and major and minor bleeding events are recorded. In addition, the principle investigator rounds in the ICU daily Monday through Friday and assesses bleeding during therapy. Major bleeding was defined as a drop in hemoglobin of greater than 2 g/dl in 24 h, requiring transfusion on 2 consecutive days, or any major bleed as perceived by the intensivist caring for the patient.
2.1. Study design and data collection Using a retrospective cohort study design, patients with concomitant orders for both TH and IVUH were identified through the pharmacy database (Med Manager, Cerner, Inc.). Patients in the ICU, on TH were monitored closely by the heparin dosing service. The following baseline variables were recorded: age, gender, height, actual body weight (ABW), body mass index (BMI), ideal body weight (IBW), adjusted body weight (AjBW), the acute physiology and chronic health evaluation (APACHE) II score at the time of heparin initiation, indication for UH, initial heparin dose in units/kg/h, and baseline coagulation tests (aPTT, prothrombin time (PT) and international normalized ratio (INR). 2.2. Heparin dosing and coagulation testing All patients were required to have at least 6 h of IVUH and one corresponding aPTT drawn during TH to be included in the analysis. Data was grouped into three distinct temperature ranges: baseline (pre-hypothermia), TH (up to 3 aPTT readings drawn while core body temperature was 33 ◦ C), and post-re-warming (≥37◦ C). All coagulation testing was performed by the Detroit Medical Center’s Core Hematology STAT lab, and samples were sent in blue-top tubes for analysis. The DMC uses the fully automated, Sysmex® CA 1500 coagulation system for aPTT analysis. The majority of aPTT results are reported in the ICU within 30–45 min. The upper aPTT limit for reporting is 200 s. For the purposes of statistical analysis, all measurements reported as >200 s were rounded to 200 s. Anticoagulation therapy is managed by the DMC pharmacy department and adjustments to IVUH rates were performed by a 24-h pharmacy dosing service according to established dosing nomograms.9 All dose adjustments, including interruptions in the IVUH infusion were recorded and reported. The DMC utilizes a comprehensive electronic medical record, with electronic physician order entry, and barcode scanning for medication administration. Heparin dosing requirements were documented as units/kg/h based on total body weight, unless the body mass index was >30 m2 . In these cases, an adjusted body weight ([actual weight − ideal body weight][0.4] + IBW) was used for dosing. Therapeutic aPTT was defined as aPTT of 1.5–2 times baseline aPTT (s).
2.4. Statistical analysis Continuous variables were expressed as mean ± standard deviation for normally distributed variables. Chi-square or Fisher’s exact test were used to compare categorical variables, as appropriate. For purposes of analysis, the temperature readings with corresponding aPTT and heparin rates were grouped into three distinct subsets: baseline, TH and post-re-warming. Descriptive statistics were performed on aPTT and heparin rates during the 3 temperature points. A Bartlett’s test was performed to test for equal variances between groups. An ANOVA test was performed to test for significance of heparin dose and aPTT among the 3 groups and a Bonferroni post hoc analysis was performed to identify differences between groups. A multinomial logistic regression analysis was performed to test for PTT differences between the three phases. The variables of age, sex, BMI, heparin rate and APACHE score were tested for significance between groups. The p-values were calculated using a two-sided analysis, and the level of significance was set at 200 s, and the other patient had two consecutive readings of >100 s. In all cases, heparin was discontinued. 4. Discussion The safety of systemic anticoagulation therapy during TH is an area of controversy. Coagulopathy itself is often viewed as a relative contraindication for TH. However, in cases of sudden cardiac death associated with thrombotic events, including pulmonary embolism and acute myocardial infarction, systemic anticoagulation remains the mainstay of therapy. Under normal conditions, heparin is bound to antithrombin, which ultimately causes inactivation of thrombinmediated conversion of fibrinogen to fibrin.10 Intravenously UH has a relatively short half-life and can be reversed with protamine, offering it some advantages in critically ill patients. Heparin’s clearance is saturable and may be highly effected by temperature.10 In
K.A. Wahby et al. / Resuscitation 85 (2014) 533–537
aPTT (seconds)
aPTT
Heparin Rate
160
16
140
14
120
12
100
10
80
8
60
*Target aPTT range
6
40
4
20
2
0
Heparin Rate (Units/kg/hr)
536
0 Baseline
TH
Post Re-warming
aPTT: activated partial thromboplastin time; TH: therapeutic hypothermia; kg: kilograms; hr: hour *The Detroit Medical Center's anticoagulation protocol typically targets aPTT=48 to 78 seconds
Fig. 2. Heparin rate and response.
addition, since the clotting cascade depends on multiple enzymatic processes leading to thrombin production, the entire cascade may be altered under hypothermic conditions.11 This mechanism would explain the elevated aPTTs and prolonged periods of interruption before aPTT fell to a normal treatment range. Therapeutic hypothermia gained worldwide support after two landmark studies were published in the New England Journal of Medicine in February 2002.1,2 In the major trial of 275 patients with cardiac arrest, TH improved neurological outcome when patients were cooled to 32–34 ◦ C for 24 h.1 In this study 55% of the patients in the hypothermia group had favorable neurologic outcome at 6 months, compared to 39% in the normothermia group (risk ratio, 1.40 (CI 1.08–1.81). Mortality was also significantly less in the hypothermia group, 41% vs 55%, p = 0.02, RR, 0.74 (CI 0.58–0.95). Bleeding rates through day 7 were 26% and 19% in the TH and normothermia groups, respectively, however, coagulation testing and anticoagulant medications were not described. In the other trial by Bernard et al., cooling was induced quicker, but sustained for only 12 h which may limit the pharmacodynamic and pharmacokinetic alterations.2 In our study, all patients were on IVUH and most exhibited a dramatic response to IVUH expressed as aPTT elevations, and prolonged periods of interruption in the UH infusion before the aPTT fell back into a target range. 250
Heparin Dose (Units/kg/hr)
aPTT (seconds)
200
In our study, only 3 patients achieved aPTT in the target range after initial dosing, and the dose of IVUH in these three patients was lower than standard dosing protocols, suggesting that over time, increased awareness of our findings led to more conservative dosing strategies. It is important to point out that we had 5 patients in our study who were already fully anticoagulated with heparin prior to cardiac arrest. These patients served as their own control, and all 5 patients showed significant elevations in aPTT despite pre-TH values that were all in the target range. Our hospital performs quarterly quality analysis of 100 randomly selected patients, managed by the heparin dosing service. Upon review of our 2012 data, 68% of patients achieved aPTTs in the target range at 24 h, 22% were below and 10% were above, and very rarely were aPTTs > 200 s. In our subset of patients, at 24 h into the TH protocol, 10 (22%) patients achieved target aPTT, which emphasizes the challenges that we face with current heparin dosing protocols during TH. Other pharmacokinetic and pharmacodynamic parameters may be significantly altered during TH, specifically, reduced drug clearance.6–8 Limited data suggests altered pharmacokinetic profiles for some of the commonly used ICU medications including fentanyl, morphine, benzodiazepines, and the neuromuscular blocking agents.6–8 Bjelland et al. proved that the clearance of morphine, fentanyl and propofol were all significantly lower during TH.7
150
100
50
20 15 10 5 0
0 Baseline
TH Fig. 3. aPTT results.
Post Re-warming
Baseline
TH
Post Re-warming
Fig. 4. Heparin dosing requirements.
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Cohen et al. studied plasma heparin levels in patients undergoing cardiopulmonary bypass and showed that mean heparin plateau levels increased during hypothermia with each heparin bolus administered.12 Insignificant decay was cited as the rationale. Once re-warmed, heparin levels declined linearly, at a rate proportional to the starting heparin level. In our study, heparin rates increased significantly after re-warming in order to achieve, or maintain the target level of anticoagulation, a similar finding to the Cohen study. The only other published study assessing anticoagulation with heparin in patients on mild TH post-cardiac arrest was performed by Spiel et al.13 They assessed 18 patients on TH, induced by cold IV fluids, and receiving therapeutic anticoagulation with either IVUH (n = 16) or enoxaparin (n = 2). They reported a 2.7-fold increase in aPTT from baseline. The aPTT did not return to normal until 24 h after TH was complete. The graphic display of aPTTs in this study shows aPTT 1 h after TH was approximately 140 s, similar to our findings. This suggests a rapid effect of TH on heparin pharmacodynamics. No bleeding events were recorded in this study, a significant finding considering that many clinicians would question application of TH in patients fully anticoagulated prior to cardiac arrest. The study did not report heparin rates or dosing strategies. The small sample size in this study may have failed to detect significant bleeding events. Whether TH alone increases bleeding risk remains controversial. Prolongation of bleeding times and reduced thromboxane concentrations have been seen during TH.14 However, in a recent meta-analysis, bleeding was not significantly different between the cooled patients and normothermic patients.15 We assessed a random cohort of our critically ill patients, on the same TH protocol, during the study period and found no significant increase in aPTT from subcutaneous heparin for VTE prophylaxis. Patients in both groups had similar APACHE II scores. It is important to point out our study limitations. While this is the first study to look at IVUH dosing in TH, we have adjusted dosing strategies in some patients over time due to increased awareness of the elevated aPTT phenomenon. Thus, not all patients were dosed according to strict protocol guidelines. All patients, however, were followed by our pharmacy anticoagulation team and by clinical pharmacy specialists who round daily in the ICU with a multidisciplinary team and inquire daily about bleeding events, etc. While retrospective in nature, patient profiles are saved and bleeding events are noted on our monitoring sheets. Secondly, the lack of plasma heparin concentrations to correlate our findings with the pharmacokinetics of heparin is a significant limitation. We suspect that heparin metabolism and clearance are both reduced, but without drug levels, we are unable to prove this. The sensitivity of the aPTT testing must be acknowledged. Since the upper limit for the machine is 200 s, for the purpose of our statistical analysis, these were rounded to 200 s. This may falsely lower the true rise in aPTT. Therefore, the change in aPTT from baseline may actually be higher than our estimates. Finally, the best test for monitoring anticoagulation during TH is not clear. It is possible that thrombin time, heparin levels, or activated clotting time may be more predictable tests during TH, but this is not the standard of care for monitoring heparin in most hospitals in the United States. Our institution has since created a modified heparin dosing protocol (40 units IV bolus, followed by 7 units/kg/h) for use during TH. Data collection to validate the effectiveness of this protocol is ongoing. 5. Conclusion The beneficial effects of TH are substantial, and include neuroprotection mediated by a reduction in cerebral metabolism of glucose and oxygen, reduced cerebral edema, decreased
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thrombotic risk, and electrical stabilization of the brain.6 These beneficial effects must be weighed with the knowledge that TH also exerts physiologic alterations throughout the body. More and more data is available which supports dosage reductions for commonly used medications in the critically ill during TH. Lacking to this body of evidence is dosing recommendations for IVUH, a drug with a narrow therapeutic range and risk for toxicity in these patients. This study highlights a concerning issue in the care of critically ill patients undergoing therapeutic hypothermia and provides evidence that dosing recommendations for heparin during TH need to be modified to account for reduced drug clearance. Our study would support a modified dosing protocol for IVUH during TH, with careful monitoring and adjustment of heparin rates during and immediately after TH. Funding source No funding was provided for this study. Conflict of interest statement The authors of this manuscript have nothing to disclose. Acknowledgments The authors would like to acknowledge Dr. Haithem A. ElHaddad for his help with data collection, and the DMC Pharmacy Anticoagulation Service for their outstanding assistance with monitoring these patients. References 1. Holzer M, Cerchiari E, Mertens P, et al. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. 2. Bernard A, Gray TW, Buist MB, et al. Treatment of comatose survivors of out of hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 3. Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1. Indications and evidence. Intensive Care Med 2004;30:556–75. 4. Nolan JP, Morley PT, Vanden Hoeck TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the advanced life support task force of the international liaison committee on resuscitation. Circulation 2003;108:118–21. 5. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: Post cardiac-arrest care: 2010 American Heart Association guidelines for cardiopulmonary arrest and emergency cardiovascular care. Circulation 2010;122:S768–86. 6. Van den Broek MPH, Groenendaal F, Egberts ACG, Rademaker CMA. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 2010;49: 277–94. 7. Bjelland TW, Klepstad P, Haugen B, Nilsen T, Dale O. Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Drug Metab Dispos 2012 [Epub ahead of print; October 13]. 8. Fukuoka N, Aibiki M, Tsukamoto T, et al. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic hypothermia. Resuscitation 2004;60:225–30. 9. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a standard care nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874–81. 10. Reed RL, Bracey AW, Hudson JD, et al. Hypothermia and blood coagulation: dissociation between enzyme activity and clotting factor levels. Circ Shock 1990;32:141–52. 11. Rohrer M, Natale A. Effect of hypothermia on the coagulation cascade. Crit Care Med 1992;20:1402–5. 12. Cohen JA, Frederickson EL, Kaplan JA. Plasma heparin activity and antagonism during cardiopulmonary bypass with hypothermia. Anesth Analg 1977;56:564–9. 13. Spiel AO, Kliegel A, Janata A, et al. Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids. Resuscitation 2009;80:762–5. 14. Valeri RC, MacGregor H, Cassidy G, et al. Effects of temperature on bleeding time and clotting time in normal male volunteers. Crit Care Med 1995;23:698–704. 15. Xiao G, Guo Q, Shu M, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and metaanalysis. Emerg Med J 2013;30:91–100.
