Brief Reports

Critical care checklists, the Keystone Project, and the Office for Human Research Protections: A case for streamlining the approval process in quality-improvement research*

Richard H. Savel, MD, FCCM; Evan B. Goldstein, DO; Michael A. Gropper, MD, PhD, FCCP

Checklists have been recently promulgated as a method to ipating hospitals in as well as for not having obtained enhance and improve outcomes for critically ill informed consent from each patient and clinician involved in the patients. Specifically, recent work performed by researchers from project. This article documents the recent events surrounding the the Johns Hopkins Medical Institutions has demonstrated that the Keystone Project and the response to the actions taken by the addition of checklists to usual care in the intensive care unit is Office for Human Research Protections in the lay press and the associated with a decrease in the incidence of catheter-related new media (Internet and blogs), articulates how a determination bloodstream infections. Initially evaluated at the institutional can be made if a project is quality-improvement, human-subjects level, this effort has been successfully expanded to the state level research, or both, and proposes some solutions to create a as part of the Michigan Keystone Project. Although this work has structured approach to this kind of research in the future. (Crit recently received significant positive attention in the lay press, Care Med 2009; 37:725–728) the Office for Human Research Protections—as they felt that this KEY WORDS: informed consent; quality improvement; human was a research project requiring Institutional Review Board ap- subjects research; Keystone Project; catheter-related blood- proval and informed consent—put the data collection on hold for stream infection; checklists; new media; blogs lack of approval by the Institutional Review Board at the partic-

hecklists—important remind- els (3, 4); currently, these initiatives are fections dropped significantly and re- ers providing much-needed beginning to gain attention in the lay mained low (3). These checklists were an structure in complex environ- press (5, 6). attempt to enhance compliance with an ments—are one of the tools The purpose of this article is to review, approach recommended by both the Cen- recommendedC to improve patient safety discuss, and explain the distinction be- ters for Disease Control and Prevention outcomes in the intensive care unit (ICU) tween quality improvement (QI) and QI as well as the Institute for Healthcare (1). Although checklists have been used research, the controversies surrounding Improvement and included the following: to enhance safety in other fields for some the manner in which QI research is cur- hand washing, using full-barrier infec- time (most notably in the aerospace in- rently conducted, and the role of the Of- tion precautions during catheter inser- dustry and the military [2]), their pres- fice for Human Research Protections tion, cleaning the patient’s skin with ence in health care has only recently be- (OHRP) in the structure of these trials— chlorhexidine, avoiding (whenever possi- come prominent. Implementation of ICU specifically presenting the recent case of ble) the femoral site for line placement, checklists has been successfully docu- the Keystone Project in Michigan, and and removing unnecessary catheters in a mented at the institutional and state lev- the temporary cessation of data collection timely fashion. This project was described because of a perceived lack of regulatory as a prospective cohort study with a con- evaluation and proper informed consent current control ICU, and the Institutional *See also p. 791. (IC). In addition, we describe the strong Review Board (IRB) at the Johns Hopkins From the Department of Critical Care Medicine reaction on the Internet to the termina- Medical Institutions approved the study, (RHS), Montefiore Medical Center, Bronx, NY; Depart- tion of this project and propose several with a waiver for IC being granted (3). ment of Surgery (EBG), Maimonides Medical Center, possible solutions to this research conun- In an analogous—albeit much larger— Brooklyn, NY; and Department of Anesthesia/Critical drum. Care Medicine (MAG), University of California San Fran- study, this same group worked with the cisco School of Medicine (UCSF), San Francisco, CA. Michigan Health and Hospital Associa- Dr. Gropper is the Director of Critical Care Medi- The Keystone Project tion to implement checklists in ICUs cine at UCSF, Vice Chairman of the Department of Anesthesia for Clinical Quality, and a Professor of Dr. Peter Pronovost and his group at throughout that entire state (the Key- Anesthesia and Physiology at UCSF. Johns Hopkins have been at the forefront stone Project). Again, Pronovost was able The authors have not disclosed any potential con- in the academic analysis of the use of to demonstrate that the Institute for flicts of interest. Healthcare Improvement/Centers for Dis- For information regarding this article, E-mail: checklists in the ICU in an attempt to [email protected] improve outcomes. Their landmark 2004 ease Control and Prevention checklists Copyright © 2009 by the Society of Critical Care study demonstrated that by adding could be implemented, and their use was Medicine and Lippincott Williams & Wilkins checklists to standard ICU practice, the associated with a persistent decrease in DOI: 10.1097/CCM.0b013e31819541f8 rate of catheter-related bloodstream in- catheter-related bloodstream infections

Crit Care Med 2009 Vol. 37, No. 2 725 (and, presumably, saved lives). The Johns cally, concerns were raised that QI they received a letter of complaint alleg- Hopkins IRB made a determination that projects (both current and future) might ing that research was being performed the study would be exempt from IRB eval- be construed as human-subjects research that potentially violated federal regula- uation, and IC was waived (4). Of note, (HuSR) if patient data were collected and tions; they investigated and discovered the project was performed without ap- actions taken by the result of these data. that research was, in fact, being per- proval from local IRBs (local approval was The wording of a statement from the formed without IC; finally, Johns Hop- not sought) as well as in some small OHRP in response to numerous letters to kins postponed any further data collec- hospitals where an IRB did not exist. Ad- the organization did little to alleviate tion until a full investigation could be ministrators in participating Michigan these concerns: completed. There are significant differ- hospitals, however, were aware that this “As stated above, the regulations do ences, however, between this project and project was happening, as it was ap- not apply when institutions are only im- more traditional HuSR, including: 1) the proved by (and actually being per- plementing practices to improve the risks to the patient of being in the project formed with assistance from) the Mich- quality of care. At the same time, if insti- (minimal to zero); 2) the risks of not igan Health and Hospital Association. tutions are planning research activities improving compliance with patient safety The decisions made by the Hopkins IRB examining the effectiveness of interven- guidelines (significant); 3) the impracti- to have the study be exempt from re- tions to improve the quality of care, then cability of performing IC (both for the view and not require local IRB approval the regulatory protections are important patients and potentially the clinicians) were (in retrospect) controversial and to protect the rights and welfare of hu- given the number of hospitals involved, will be discussed further below. man research subjects ...”(11, 16). the necessity of these interventions, and Such vague statements continue to the difficulties of gaining IC in critically Checklists in the Lay Press fuel the strongly worded, somewhat emo- ill patients or their surrogates, in general; tional, academic debate and discourse re- and 4) the fact that the interventions Approximately 1 year after the Key- garding what, in fact, constitutes QI/ being performed could have been (some stone Project results were published, Atul HuSR and what sorts of regulatory would argue should have been) intro- Gawande, MD (a noted Harvard surgeon), protections will be required. duced into clinical practice without ei- wrote a piece entitled “The Checklist” in In mid-February 2008, after much ther IRB approval or IC. These distinc- the December 10, 2007, edition of The pressure from various medical societies, tions are important, and are the primary New Yorker, focusing on the important, including a letter signed by five medical rationale as to why this kind of QI re- often unrecognized, value of the multi- and nursing organizations (17), the search should be handled in a different disciplinary critical care team; specifi- OHRP came out with another statement, regulatory fashion. cally, he expounded on the manner in in which their stand on the issue appears which the aforementioned checklists en- to have changed: hance patient safety in the ICU (5). This “We do not want to stand in the way of Distinguishing QI from HuSR article garnered significant discussion in quality improvement activities that pose both the traditional and the new media minimal risks to subjects. . . . [OHRP] Fundamentally, QI is felt to be an in- (Internet and blogs) (7–11). regulations provide great flexibility and tegral part of the ongoing management of A mere 3 weeks later, in the December should not have inhibited this activity the system for delivering clinical care, 30, 2007, edition of the New York Times, .... Such research would likely have when compared with HuSR, which can be Dr. Gawande broke yet another story re- been eligible for both expedited IRB re- defined as a knowledge-seeking enter- volving around checklists and patient view and a waiver of the informed con- prise that is independent of routine med- safety in the ICU: the OHRP had an- sent requirement. ical care (19). The essential distinction is nounced the termination of any further . . . the Johns Hopkins project has that QI exists to ensure that patients are data collection involving the Michigan evolved to the point where the interven- receiving a standard of care, whereas the Keystone Project (12). OHRP claimed tion, including the checklist, is now be- primary focus on HuSR is to find gener- that by not obtaining explicit IC from ing used at certain Michigan hospitals alizable knowledge and define a new stan- each patient and provider involved in the solely for clinical purposes, not medical dard of care (20). Clinicians are under an project, the Hopkins researchers had vi- research or experimentation. Conse- obligation to perform QI, and it is widely olated fundamental scientific and ethical quently, the regulations that govern hu- accepted that IC is not necessary. For research regulations (13, 14). man subjects research no longer apply example, ICUs collect information re- With this simple statement, the OHRP and neither Johns Hopkins nor the Mich- garding infection rates, complications, sparked significant heated debate, with igan hospitals need the approval of an and medication errors—data that are heels dug in firmly on both sides of the IRB to conduct the current phase of the considered confidential and subject to controversy. Numerous academic experts project” (18). Health Insurance Portability and Ac- in the field of QI research voiced their Although this statement articulated countability Act regulations—all without opinions throughout the blogosphere, that the current phase of the Keystone IC (although much of the data collected siding with regional and national hospital Project could resume, the letter stopped in ICUs for QI is deidentified and/or pa- associations, strongly opining that this short of clarifying the problems that led tient identifiers are not included in the ruling was “absurd” and should be to the research interruption in the first data collection process). In general, changed immediately (7–11, 15). Clearly, place and did little to help guide the ap- HuSR does require IC, as participation is numerous healthcare organizations were proval process in the future. voluntary; patients must have the ability troubled by the potential negative rami- On the surface, the actions taken by to opt out of HuSR if they do not wish to fications of this federal action: specifi- the OHRP appear to be understandable: partake.

726 Crit Care Med 2009 Vol. 37, No. 2 What is an institution to do when a nal, logical approach to the ethical and reg- projects have a rigorous, scientific, and project has components of both QI and ulatory issues surrounding this case. The evidence-based underpinning. HuSR? Certain thought-leaders feel that first issue that is addressed is as follows: such projects should come under the ru- should the Johns Hopkins IRB have bric of HuSR and be treated as such— deemed the research to be exempt from Conclusion and potentially requiring IC and evaluation by IRB evaluation. The consensus is that, in Recommendations an IRB (19). Determining when a project fact, it should have undergone review. is more than just QI and has character- Both sets of ethicists believe (and it is It is imperative that a middle-ground istics of HuSR can sometimes be difficult. the opinion of the authors), however, approach be found for approval of large- Baily and coworkers (19, 20) have made that it would have been more than ac- scale QI/HuSR to prevent laudable recommendations that a study may be ceptable from a regulatory and ethical projects, such as the Keystone, from be- QI/HuSR if it has any of the following standpoint to have it evaluated in an ing shut down in the future. It is often qualities: 1) randomization of patients expedited fashion and that approval difficult to generate institutional support into different intervention groups to en- from a central IRB such as this would for local QI projects, and actions such as hance confidence in differences obscured have been sufficient: it was not deemed those taken by the OHRP will have a by nonrandom selection; 2) testing of is- necessary to get approval from each and chilling effect on these important efforts. sues that are beyond current science and every hospital for this particular kind of Our recommendations include the fol- experience, such as new treatments; 3) project. lowing: 1) the OHRP must develop new delayed or ineffective feedback of data The second, and clearly more impor- ways to help institutions streamline the from monitoring the implementation of tant, issue in this case is the role of IC. approval process of QI/HuSR by design- changes; and 4) the involvement in key Again, with consensus, these prominent ing and developing structured criteria as project roles of researchers who have no bioethicists state that the way to best to what constitutes “impracticability” of ongoing commitment to improvement of answer this question is to focus on the protocols without waivers of consent and the local care situation. It has also been purpose of IC: to protect subjects from “minimal risk” to the subjects, as well as recommended—given many of the differ- whatever risks may be inherent in the providing some guidance for multicenter ences between traditional HuSR and QI/ research project itself. The use of check- QI/HuSR projects like Keystone (includ- HuSR—that institutions consider form- lists to enhance compliance with agreed- ing QI-IRBs, with a focused interest in upon patient-safety best practices posed ing an explicit policy for central IRB ap- evaluating these sorts of projects (19). no threat to subjects. One author goes so proval of such projects); 2) more institu- Once a decision has been made that a far as to say that this is not to be consid- tions should have formal processes project qualifies as QI/HuSR, a significant ered any kind of human subjects research within their IRBs to rapidly and safely step is determination of the necessity of at all; rather, it is to be viewed as a com- evaluate QI/HuSR, with the goal of im- IC. Under current regulations, IC can be bination of QI and research of organiza- proving patient safety, making the ap- waived if four conditions are present: 1) tional function (22). Regardless of how proval process less onerous and more ef- the research cannot “practicably be car- this kind of research is named (and as the ficient, while at all times protecting the ried out” without the waiver; 2) the sub- OHRP itself eventually concluded), a rights of the individual patient; and 3) jects’ rights and welfare will not be ad- waiver of IC appears to be appropriate hospitals too small to have their own versely affected; 3) the research involves from an ethical and regulatory stand- IRBs should be allowed to use IRBs from no more than minimal risk; and 4) sub- point, without putting humans at any predetermined designated nearby re- jects will be provided with additional per- risk. Perhaps, if the Hopkins IRB had gional centers of excellence. tinent information after participating. It evaluated the study and provided such a Given the intense and impassioned is beyond the scope of this article to de- waiver, the OHRP might not have inter- reaction (in the lay press, as well as on termine when it is “not practicable” to rupted the Keystone Project. These regu- blogs throughout the Internet) both to perform a research project without a lations, however, can often be difficult to the impressive results shown by Dr. waiver, and it should be beyond the scope interpret. As stated by Baily, “The fact Pronovost’s checklist research, as well of the principal investigator of a project that a sophisticated IRB interpreted the as the termination of his important to define what constitutes “minimal risk” regulations differently from the OHRP is project by the OHRP, there is clearly a (19). Federal agencies, such as OHRP, a bad sign in itself. You know you are in real demand for large-scale QI/HuSR to should provide guidance and assist re- the presence of dysfunctional regulations proceed—creating new, better stan- searchers and IRBs with these determina- when people cannot easily tell what they dards of care for our hospitalized pa- tions, in the form of clear, easy-to- are supposed to do” (22). understand, well-structured guidelines. Although the risks to the subjects tients. With a sense of urgency and fo- The crux of the ethical argument has were little to none (and it has been ar- cused determination, leaders in been discussed in two articles recently gued that there may have been more of a academia and government must meet published in the New England Journal of risk of not being involved in the trial) to create a structured approach to this Medicine by prominent ethicists from the (21), the presence of minimal risk should kind of research, allowing much- National Institutes of Health, and the Hast- by no means minimize the value and ne- needed innovation to flourish unim- ings Center (21, 22): that in the name of cessity of such research. This field of peded while simultaneously protecting protecting patients, the actions of the study—although it is new and still in the the rights of individual patients. OHRP may have had the potential to do process of having the optimal regulatory Hear Dr. Savel interview Dr. Prono- more harm than good. Both groups came approaches worked out—is crucial to en- vost as part of the 100th icritical care to similar conclusions and provide a ratio- sure that national quality-improvement podcast at http://www.sccm.org/podcast

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728 Crit Care Med 2009 Vol. 37, No. 2 Unexplained hypotension: The spectrum of dynamic left ventricular outflow tract obstruction in critical care settings*

Anand Chockalingam, MD; Smrita Dorairajan, MD; Meenakshi Bhalla, MD; Kevin C. Dellsperger, MD, PhD

Objective: To illustrate the clinical and hemodynamic abnor- catheterization excluded acute coronary disease. In critical care malities caused by dynamic left ventricular outflow tract obstruc- setting, LVOTO can occur due to apical ballooning syndrome, tion (LVOTO) in critical care setting. coronary disease, medications, volume depletion, and valvular Design: We reviewed cases referred to Cardiology with echo- abnormalities. Because this condition mimics acute coronary cardiographic evidence of LVOTO and their clinical presentations. syndrome or other etiologies of hypotension in medical and sur- We present those cases where LVOTO can transiently occur with- gical intensive care units, appropriate treatment can be delayed. out hypertrophic cardiomyopathy when inotropic agents are used Nonhypertrophic cardiomyopathy LVOTO usually responds well to for hypotension. fluid replacement, beta blockers, and medication changes. Measurements and Main Results: Five women in the 50–70 Conclusions: LVOTO should be suspected especially in women age range and prior history of hypertension presented with vari- presenting with hypotension and systolic murmur in critical care ous symptoms like chest discomfort, fatigue, dizziness, atrial settings. Clinical acumen and timely echocardiography are re- fibrillation, and hypotension. An ejection systolic murmur was quired to effectively counter this transient but potentially lethal noted most often in the left third intercostal space and ECG problem. (Crit Care Med 2009; 37:729–734) revealed ST-T wave abnormalities. LVOTO caused by mitral sys- KEY WORDS: left ventricular outflow tract obstruction; acute tolic anterior motion was detected by echocardiography and myocardial infarction; hypotension; shock

ynamic left ventricular out- critically ill patients. Our institutional re- giography confirmed patent coronaries flow tract obstruction (LVOTO) view board waived the need for approval within the hour. An echocardiogram 3 is typically associated with for this study. months later showed persistent chordal hypertrophic cardiomyopa- SAM with peak LVOT gradients of 50 mm Dthy (1, 2). As systole progresses, the an- Report of Patients Hg. The patient did well clinically on terior mitral leaflet (AML) is drawn to- atenolol 100 mg/day with arthritis- ward the hypertrophied basal ventricular Patient 1. A 68-year-old white woman related functional limitations only. A year septum. This leads to subaortic stenosis with hypertension, asthma, and rheuma- later, she underwent a lengthy surgery that increases throughout systole pro- toid arthritis presented to the emergency for vertebral fracture stabilization and ducing a characteristic late peaking echo room with fatigue and dizziness. Dobut- once again became hypotensive. ECG amine (5 ␮g/kg/min) was started for hy- Doppler profile. Independent of hypertro- confirmed LVOTO up to 120 mm Hg and potension of 80/50 mm Hg. Electrocar- phic cardiomyopathy, left ventricular this time she had LV dysfunction, ejec- diogram (ECG) revealed anterior ST-T (LV) hypertrophy and increased cardiac tion fraction 30% with akinesia of the changes suggestive of ischemia and tro- contractility can cause dynamic LVOTO distal and apical LV segments. She re- ponin I elevation to a peak of 5.1 ng/mL. (3–7). Besides being a coincidental phe- sponded to medical management with nomenon of academic curiosity, the fol- A grade 3/6 ejection systolic murmur in the left third intercostal space and suspi- fluids and intravenous metoprolol once lowing situations illustrate the clinically again. The latest echocardiogram 3 central role played by dynamic LVOTO in cion of cardiogenic shock lead to a bed- side echocardiogram in the emergency months later confirmed normalization of room. Two-dimensional imaging revealed LV function (Fig. 1). On atenolol 100 mg daily, her resting and stress (dobutamine *See also p. 793. overall preserved systolic function with From the Division of Cardiovascular Medicine, De- an ejection fraction of 55%, normal LV 50 mcg/kg/min) gradients were 30 and 50 partment of Internal Medicine (AC, SD, MB, KCD), wall thickness without septal hypertro- mm Hg, respectively. University of Missouri School of Medicine, Columbia, phy, and systolic anterior motion (SAM) Patient 2. A 79-year-old white woman MO; and Cardiology Section (AC), Harry S Truman VA with hypertension and arthritis presented Medical Center, Columbia, MO. of the chordal apparatus of the AML. Dis- Supported, in part, by Department of Veterans continuation of dobutamine, a saline in- with exertional chest tightness and dys- Affairs, VISN 15 Research Award. travenous bolus, and closely supervised pnea. Vitals were stable and a 3/6 ejection The authors have not disclosed any potential con- administration of 15 mg metoprolol in- systolic murmur was noted at the left flicts of interest. sternal border. ECG showed LV hypertro- For information regarding this article, E-mail: travenously within 15 minutes reduced [email protected] the murmur to 1/6 intensity and the phy with T inversions and peak troponin Copyright © 2009 by the Society of Critical Care LVOTO from 150 to 40 mm Hg. Blood I of 0.44 ng/mL (normal Ͻ0.05). Coro- Medicine and Lippincott Williams & Wilkins pressure improved to 100/70 mm Hg and nary angiography showed luminal irreg- DOI: 10.1097/CCM.0b013e3181958710 cardiac catheterization with coronary an- ularities and an 80% lesion in mid-

Crit Care Med 2009 Vol. 37, No. 2 729 Figure 1. Top: Patient 1 Doppler echo image showing peak left ventricular outflow tract (LVOT) gradient of 112 mm Hg at initial presentation in November, 2006 with normal left ventricular (LV) function (left). Repeat Doppler study 30 minutes later with reduction of peak gradient to 34 mm Hg of Dobutamine, following metoprolol intravenously and saline intravenous bolus (right). Bottom: Same patient in December, 2007, 2D echocardiography in apical long-axis view end systolic frame showing chordal systolic anterior motion (SAM) and anteroapical akinesia (left). Repeat study 3 months later documenting normalization of systolic function (right). posterior descending artery. Catheter vere LV dysfunction suggestive of ABS was discontinued because theoretically pullback and echocardiogram confirmed with pullback LVOT gradient of 70 mm its inotropic action could aggravate apical ballooning syndrome (ABS) with Hg. Echocardiogram showed basal hyper- LVOTO. Intravenous normal saline was LVOTO and a peak gradient of 60 mm contractility and SAM of the AML with initiated totaling 3–4 L/day over the next Hg. We believe in this patient LV basal severe LVOTO. She was discharged the 3 days along with metoprolol 5 mg intra- hypercontractility as a compensatory next day on metoprolol, and repeat echo- venously every 4–6 hours. Hypotension mechanism for the ABS-related severe cardiogram in 2 weeks showed normal LV resolved in 1 hour, atrial fibrillation re- apical dysfunction resulted in transient function and absent LVOTO. verted to sinus rhythm spontaneously in SAM and development of LVOTO. Metopro- Patient 4. A 76-year-old woman was 3 hours. LVOTO murmur persisted for lol 50 mg twice daily was initiated and re- admitted to the intensive care unit with two more days. Repeat echocardiogram peat echocardiogram 3 months later re- ischemic cerebrovascular accident and after 2 weeks showed no evidence for vealed normalization of LV function and no intubation for airway protection. Cardiol- LVOTO. evidence for LVOT obstruction. ogy was consulted on the 3rd hospital day Patient 5. A 79-year-old white woman Patient 3. A 52-yr-old white woman for new onset tachycardia and hypoten- was evaluated for new onset systolic mur- with history of hypertension and depres- sion. She was found to be in rapid atrial mur with hypotension in the surgical in- sion presented with anginal discomfort fibrillation with ventricular rate of about tensive care unit. She had undergone re- that started 18 hours earlier. Vitals were 150/min, blood pressure of 80/50 mm Hg peated laparotomies for colon cancer and stable and a grade 2/6 ejection systolic with a 3/6 ejection systolic murmur was intubated for airway support on day murmur was noted at the left sternal noted in the left 3rd intercostal space. 21 of hospitalization. Echocardiogram border. ECG showed anterior deep T in- Troponin was borderline at 0.10 ng/mL showed a small LV chamber, mild con- versions and peak troponin I of 0.95 (normal Ͻ0.05). Bedside echocardiogram centric LV hypertrophy, hyperdynamic ng/mL (normal Ͻ0.05). Coronary angiog- showed SAM of the AML with LVOTO and LV contractility with ejection fraction raphy showed normal coronaries with se- a peak gradient of 145 mm Hg. Digoxin over 85%. Color Doppler suggested mid-

730 Crit Care Med 2009 Vol. 37, No. 2 cavity level LV outflow obstruction and DISCUSSION reversal of their hypotension if dynamic pulse wave Doppler confirmed peak gra- LVOTO is the underlying cause. Figure 2 dient of about 40 mm Hg at the mid-cavity These patients represent only those outlines the various underlying condi- level. She responded to intravenous fluids cases we recognized with dynamic tions and characteristics that may play a initially. Three days later, she was started LVOTO developing in the critical care en- role in initiating dynamic LVOTO. on dopamine for hypotension, and murmur vironment (emergency room, surgical, or Trauma, bleeding, diuretics-related increased without clinical improvement. medical intensive care units). We share volume depletion, or any condition that Carefully initiating beta blockers and con- these illustrated cases in belief that pa- results in a reduction of LV volume could tinued fluid hydration resolved the cardiac tients with similar presentations, if rec- be sufficient to reduce the LVOT area. In issues over the next 3 days. ognized early and treated, can have rapid patients 4 and 5, prior unrecognized hy- povolemia might have contributed to a relative reduction in LV chamber size thereby promoting the Venturi effect, SAM, and increasing the likelihood of LVOTO. Severe emotional stress has been shown to increase serum catecholamine levels substantially in ABS (8, 9). Approx- imately, 20% of patients with ABS dem- onstrate LVOTO (7). Although the mental or physical stress causing ABS is obscure in many instances, the resultant basal hypercontractility likely caused the LVOTO in patients 2 and 3. Acute coro- nary syndromes involving left anterior descending artery could lead to similar significant dysfunction of the apical seg- ments (5, 10, 11). Basal hypercontractil- ity tries to compensate, and this may cause dynamic LVOTO in some patients with anteroapical infarcts. Nearly all the commonly used vaso- pressors for hypotension have significant inotropic effects and possible direct tox- icity leading to myocyte damage (12–14). Figure 2. Patient—clinical factors that predispose and precipitate dynamic left ventricular outflow When initiated before ensuring adequate tract obstruction (LVOTO) arranged in pyramidal figure to depict prevalence. volume repletion, this could provide a

Table 1. Summary of background issues, cardiac testing, and final diagnosis among our patients with LVOTO

Patient/Date of Initial November 1, 2006; Presentation December, 2007 May 2, 2007 July 3, 2007 November 4, 2007 March 5, 2008

Age/sex 68/F 79/F 52/F 76/F 74/F Symptoms/initial Fatigue and Angina/ACS Angina/ACS Rapid atrial fibrillation, Rapid atrial fibrillation, impression dizziness/ACS intubated for hypotension intracranial bleed Medical history Hypertension (HTN), HTN, arthritis HTN, depression HTN without prior HTN, emphysema, rheumatoid valve disease diabetes, and obesity arthritis, asthma Hypotension Yes No No Yes Yes Peak troponin I ng/mL 5.1 0.44 0.95 0.10 1.24 Peak BNP level pg/mL 1383/2401 817 — — 3864 MR grade 0–4/4 (initial/ 2/1 1/1 1/0 2/0 1/— follow-up) SEM/peak LVOT ϩ/150 ϩ/60 ϩ/70 ϩ/145 Absent/35 gradient mm Hg RWMA (initial/follow-up) No/no (2006); Yes/no Yes/none Yes/none None/none None/none (2007) Final diagnosis Chordal SAM-related ABS with single ABS Stress-related isolated Mid-cavity obstruction LVOTO with vessel CAD transient LVOTO without SAM episodic ABS

LVOTO, left ventricular outflow obstruction; MR, mitral regurgitation; ACS, acute coronary syndrome; SAM, systolic anterior motion; HCM, hypertrophic cardiomyopathy; ABS, apical ballooning syndrome; CAD, coronary artery disease; CHF, congestive heart failure.

Crit Care Med 2009 Vol. 37, No. 2 731 “double hit”—namely hypercontractility agonists in critical care settings to relieve substrate, any one of the above insults on an already small LV chamber— heart failure and bronchospasm (15). In may be sufficient, but commonly we initiating LVOTO. our experience, a history of hypertension found several contributors to dynamic Another common combination is the was noted in nearly all the subjects with LVOTO. overuse of loop diuretics along with beta some concentric hypertrophy. In this Clinical Recognition. Dyspnea, chest discomfort, and dizziness are the com- monest presenting symptoms. Tachycar- dia is usually present due to the adrener- gic excess. Hypotension and ST-T changes in the ECG may suggest acute coronary pro- cess (ACS). The only finding that was consistently recognized was the systolic ejection murmur (Table 1). The murmur is late peaking and maximally heard in the left 3rd intercostal space. Valsalva usually augments this murmur, whereas handgrip and squatting may reduce the murmur intensity. Figure 3 lists the signs and symptoms that are attributable directly to progressively increasing sever- ity of dynamic LVOTO. Echocardiography is ideally suited to define the severity of AML SAM, and Doppler analysis quantifies the LVOTO, Figure 4. Care must be taken to isolate the LVOT Doppler signal from the con- tamination of a commonly present mitral regurgitation jet. Adjusting the gain set- tings may at times separate the lower Figure 3. Progression of clinical presentations based on increasing severity of left ventricular outflow velocity, late peaking dynamic LVOTO tract obstruction (LVOTO). The pyramidal arrangement depicts typically recognized clinical signs and Doppler signal from the symmetrical mi- symptoms we observed in our patients as depicted in bold (center). Milder forms of LVOTO may be tral regurgitation jet. Being a variable more frequent yet under diagnosed because of nonspecific symptoms (bottom), whereas severe LVOTO process, the clinician must ensure echo may be rare but could cause life-threatening complications (top). VT-VF, ventricular tachycardia, imaging is done at the time of hearing ventricular fibrillation; EMD, electro mechanical dissociation; EF, ejection fraction; MR, mitral the murmur. Also, from the systolic regurgitation; RWMA, regional wall motion abnormalities; SVT, supraventricular tachycardia. blood pressures, peak LV subendocardial wall stress can be indirectly estimated as the sum of the systolic blood pressure and the LVOT gradient. Markedly ele- vated wall stress may unfavorably shift the oxygen supply–demand curve even in the presence of normal coronary arteries. This acute subendocardial wall stress along with microvascular endothelial dysfunction caused by hypertension (with or without LV hypertrophy), diabetes, hy- percholesterolemia, and tobacco use may account for the mild to moderate tropo- nin elevations that we observed. Cardiac catheterization may still be required to exclude ACS. Catheter pull- back from the LV would identify the sub- aortic location and severity of LVOTO. For ACS to produce enough mid and api- cal segment dysfunction and compensa- tory basal hypercontractility to cause LVOTO, the culprit lesion has to be in the proximal-mid left anterior descending coronary artery territory. If significant obstructive coronary artery disease is Figure 4. Role of echocardiography in clarifying cardiac hemodynamics in critically ill patients. found, these lesions should be treated

732 Crit Care Med 2009 Vol. 37, No. 2 Table 2. Various immediate and long-term measures to counter dynamic LVOTO

Measures for Immediate Relief Long-Term Options Comments

IV beta blockers Maintenance oral beta blockers Directly reduce left ventricular outflow tract gradients by 1. Reduced inotropy 2. Slowing of heart rate 3. Reduced Venturi forces and systolic anterior motion 4. Blunting of catecholamine over activity (in apical ballooning syndrome) IV Verapamil or diltiazem Oral Verapamil or Diltiazem Effects similar to beta blockers and may be better tolerated in COPD and asthma subjects IV fluids Ensure adequate oral hydration 1. Replenishes intravascular volume always 2. Increase in volume reduces LVOTO Discontinue inotropes Avoid digoxin and cardiac stimulants Directly affects inotropy and LVOTO Discontinue ␤ agonist levalbuterol only Minimize ␤ agonist use in Directly affects inotropy and LVOTO if other measures fail to control bronchospasm/COPD bronchospasm Discontinue diuretics and nitrates Minimize to as needed use of Increases filling and cavity size diuretics and nitrates Thrombolytics/percutaneous coronary Optimize coronary artery disease Will relieve basal hypercontractility by intervention/coronary artery bypass secondary prevention augmenting apical function in coronary graft artery disease Disopyrimide or amiodarone Disopyrimide or amiodarone 1. Control tachyarrhythmias—like atrial fibrillation 2. May improve LVOTO—based on hypertrophic obstructive cardiomyopathy literature Phenylephrine infusion Blood pressure improvement by selective ␣ agonist without increasing inotropy Mitral valve repair/replacement Rarely indicated—for persistent or recurrent symptoms Hypertension—aggressive control Maximize left ventricular hypertrophy Ͻ130/80 mm Hg regression Regular exercise Improves vagal tone Stress reduction, meditation, and Reduce catecholamine surge counseling Heart rate reduction Ͻ60 bpm Reduces susceptibility for LVOTO

LVOTO, left ventricular outflow tract obstruction; COPD, chronic obstructive pulmonary disease; IV, intravenous. aggressively to reduce ischemia and ulti- monary edema, hypotension, and comor- mechanism to explain the transient myo- mately reverse the dynamic LVOTO. bidities interact with LVOTO and each of cardial “stunning” was sudden increase in Management Options. Significant LV these needs to be independently ad- wall stress caused by LVOTO. Most of the dysfunction with an ejection fraction in dressed to optimize overall outcome. Ta- common cardiac screening tools, cathe- the 30% range either due to ACS or due ble 2 outlines the interventions and their terization, and even autopsy may miss to ABS is common in subjects with mechanism of reducing the LVOTO. Long this diagnosis. We suspect “silent” dy- LVOTO. In this setting, some of the ther- term, patients should be counseled to namic LVOTO could account for some of apies that are commonly initiated for he- avoid dehydration and medical records the excess unstable angina, ACS, and modynamic instability like inotropes and should list inotropes in allergy section to even sudden cardiac deaths that occur in intra-aortic balloon may initiate or aggra- minimize future indiscriminate use. women with normal coronaries (5, 10, vate LVOTO. In many instances, it may Long-Term Prognosis. Dobutamine 11, 15). Maintenance on long-term beta not be possible to differentiate between stress echocardiography literature does blockers or calcium channel blockers LVOTO that is caused by apical dysfunc- not suggest a higher cardiovascular event may help reduce recurrence of this prob- tion from the coincidental LVOTO that is rate for “incidental” occurrence of lem. Regular exercise may improve vagal well known to occur while on inotropes. LVOTO in the absence of CAD. ABS also tone and blood pressure management Frequent auscultation is a cornerstone seems to have reasonably good prognosis. with agents that are known to regress LV for diagnosis and treatment as well as During dobutamine stress testing, an- hypertrophy may prevent future LVOTO correlating echo LVOTO gradients with teroapical akinesia occurred with devel- recurrence. the clinical situation and reviewing opment of SAM and LVOTO in one in- closely the management steps, because stance with normalization of wall motion CONCLUSIONS presentation may favor one vs. the other after SAM resolved. Coronaries were nor- as the primary issue. Mitral regurgita- mal and blood pressure response to stress In the emergency room and in critical tion, focal and global LV dysfunction, pul- was not hypertensive. Thus, the likely care units, dynamic LVOTO occurs more

Crit Care Med 2009 Vol. 37, No. 2 733 often than is recognized. Although it may genic shock. Mayo Clin Proc 1999; 74: tion. A potential mechanism of myocardial sometimes be an “innocent bystander,” it 901–906 rupture. Eur Heart J 1995; 16:1439–1442 may generate severe aortic stenosis type 5. Hrovatin E, Piazza R, Pavan D, et al: Dy- 11. Joffe II, Riley MF, Katz SE, et al: Acquired physiology in ventricles that have hith- namic left ventricular outflow tract obstruc- dynamic left ventricular outflow tract ob- erto not been exposed to such acute pre- tion in the setting of acute anterior myocar- struction complicating acute anterior myo- dial infarction: A serious and potentially fatal cardial infarction: Serial echocardiographic load elevations. Early recognition and ap- complication? Echocardiography 2002; 19: propriate medical management are and clinical evaluation. J Am Soc Echocar- 449–455 diogr 1997; 10:717–721 essential to optimize the clinical outcome 6. Chockalingam A, Tejwani L, Aggarwal K, et 12. Luria D, Klutstein MW, Rosenmann D, et al: in these settings. al: Dynamic left ventricular outflow tract ob- Prevalence and significance of left ventricu- struction in acute myocardial infarction with lar outflow gradient during dobutamine shock: Cause, effect, and coincidence. Circu- echocardiography. Eur Heart J 1999; 20: REFERENCES lation 2007; 116:e110–e113 386–392 7. Tsuchihashi K, Ueshima K, Uchida T, et al: 13. Fisher AA, Davis MW, McGill DA: Acute 1. Braunwald E, Lambrew CT, Rockoff SD, et al: Transient left ventricular apical ballooning myocardial infarction associated with albu- Idiopathic hypertrophic subaortic stenosis. I. without coronary artery stenosis: A novel terol. Ann Pharmacother 2004; 38: A description of the disease based upon an heart syndrome mimicking acute myocardial 2045–2049 analysis of 64 patients. Circulation 1964; infarction. Angina Pectoris-Myocardial In- 14. Cohen R, Rivagorda J, Elhadad S: Asymmet- 30(Suppl 4): 3–119 farction Investigations in Japan. J Am Coll 2. Maron MS, Olivotto I, Betocchi S, et al: Effect Cardiol 2001; 38:11–18 ric septal hypertrophy complicated by dy- of left ventricular outflow tract obstruction 8. Wittstein IS, Thiemann DR, Lima JA, et al: namic left ventricular obstruction after intra- on clinical outcome in hypertrophic cardio- Neurohumoral features of myocardial stun- aortic balloon counterpulsation placement in myopathy. N Engl J Med 2003; 348:295–303 ning due to sudden emotional stress. N Engl the setting of anterior myocardial infarction. 3. Pellikka PA, Oh JK, Bailey KR, et al: Dynamic J Med 2005; 352:539–548 J Invasive Cardiol 2006; 18:E207–E208 intraventricular obstruction during dobut- 9. Sharkey SW, Lesser JR, Zenovich AG, et al: 15. Hochman JS, Tamis JE, Thompson TD, et al: amine stress echocardiography: A new obser- Acute and reversible cardiomyopathy pro- Sex, clinical presentation, and outcome in vation. Circulation 1992; 86:1429–1432 voked by stress in women from the United patients with acute coronary syndromes. 4. Haley JH, Sinak LJ, Tajik AJ, et al: Dynamic States. Circulation 2005; 111:472–479 Global Use of Strategies to Open Occluded left ventricular outflow tract obstruction in 10. Bartunek J, Vanderheyden M, de Bruyne B: Coronary Arteries in Acute Coronary Syn- acute coronary syndromes: An important Dynamic left ventricular outflow tract ob- dromes IIb Investigators. N Engl J Med 1999; cause of new systolic murmur and cardio- struction after anterior myocardial infarc- 341:226–232

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