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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq Bras Cardiol</journal-id>
      <journal-id journal-id-type="publisher-id">abc</journal-id>
      <journal-title-group>
        <journal-title>Arquivos Brasileiros de Cardiologia</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Arq. Bras. Cardiol.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">0066-782X</issn>
      <issn pub-type="epub">1678-4170</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia - SBC</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">qjjgtRx9nWMhJTbC7KMJV9b</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2019000500573</article-id>
      <article-id pub-id-type="doi">10.5935/abc.20190078</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Brief Communication</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Continuous Intravenous Inotropes in Ward Units: Expanding Therapy Outside Intensive Care using a Safety-Oriented Protocol</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2022-7512</contrib-id>
          <name>
            <surname>Hastenteufel</surname>
            <given-names>Laura Caroline Tavares</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4207-3809</contrib-id>
          <name>
            <surname>Clausell</surname>
            <given-names>Nadine</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4413-0494</contrib-id>
          <name>
            <surname>Neyeloff</surname>
            <given-names>Jeruza Lavanholi</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-0046-836X</contrib-id>
          <name>
            <surname>Domingues</surname>
            <given-names>Fernanda Bandeira</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4932-9216</contrib-id>
          <name>
            <surname>Caballero</surname>
            <given-names>Larissa Gussatschenko</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4374-4419</contrib-id>
          <name>
            <surname>Silva</surname>
            <given-names>Eneida Rejane Rabelo da</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1523-4286</contrib-id>
          <name>
            <surname>Goldraich</surname>
            <given-names>L&#237;via Adams</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
        <aff id="aff1">
          <institution content-type="orgname">Hospital de Cl&#237;nicas de Porto Alegre</institution>
          <addr-line>
            <city>Porto Alegre</city>
            <state>RS</state>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital de Cl&#237;nicas de Porto Alegre, Porto Alegre, RS - Brazil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c1"><bold>Mailing Address: L&#237;via Adams Goldraich,</bold> Hospital de Cl&#237;nicas de Porto Alegre - Servi&#231;o de Cardiologia - Rua Ramiro Barcelos, 2350. Postal Code 90035-903, Porto Alegre, RS - Brazil. E-mail: <email>lgoldraich@gmail.com</email>
				</corresp>
        <fn fn-type="con">
          <p>
            <bold>Author contributions</bold>
          </p>
          <p>Conception and design of the research: Hastenteufel LCT, Clausell N, Domingues FB, Caballero LG, da Silva ERR, Goldraich LA; Acquisition of data: Hastenteufel LCT, Domingues FB, Caballero LG, da Silva ERR; Analysis and interpretation of the data and Statistical analysis: Hastenteufel LCT, Neyeloff JL, Goldraich LA; Writing of the manuscript: Hastenteufel LCT, Clausell N, Goldraich LA; Critical revision of the manuscript for intellectual content: Clausell N, Goldraich LA.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potential Conflict of Interest</bold>
          </p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
        </fn>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>06</day>
        <month>06</month>
        <year>2019</year>
      </pub-date>
      <pub-date date-type="collection" publication-format="electronic">
        <month>05</month>
        <year>2019</year>
      </pub-date>
      <volume>112</volume>
      <issue>5</issue>
      <fpage>573</fpage>
      <lpage>576</lpage>
      <history>
        <date date-type="received">
          <day>07</day>
          <month>09</month>
          <year>2018</year>
        </date>
        <date date-type="rev-recd">
          <day>18</day>
          <month>11</month>
          <year>2018</year>
        </date>
        <date date-type="accepted">
          <day>16</day>
          <month>01</month>
          <year>2019</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/" xml:lang="en">
          <license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>Abstract</title>
        <p>Selected clinically stable patients with heart failure (HF) who require prolonged intravenous inotropic therapy may benefit from its continuity out of the intensive care unit (ICU). We aimed to report on the initial experience and safety of a structured protocol for inotropic therapy in non-intensive care units in 28 consecutive patients hospitalized with HF that were discharged from ICU. The utilization of low to moderate inotropic doses oriented by a safety-focused process of care may reconfigure their role as a transition therapy while awaiting definitive advanced therapies and enable early ICU discharge.</p>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords</title>
        <kwd>Cardiotonic Agents</kwd>
        <kwd>Dobutamine</kwd>
        <kwd>Heart Failure/physiopathology</kwd>
        <kwd>Inotropes</kwd>
        <kwd>Milrinone</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introduction</title>
      <p>In advanced heart failure (HF), patients with low output syndrome may benefit from intravenous inotropes to provide symptomatic relief and hemodynamic support with different purposes - stabilization of the acute setting, bridge to more definitive surgical therapies for advanced disease and palliation. Among patients admitted with decompensated HF, around 12 to 14% receive inotropes.<xref ref-type="bibr" rid="B1">1</xref> However, the safety of inotrope use remains a concerning issue.<xref ref-type="bibr" rid="B2">2</xref>
			</p>
      <p>In the acute setting, continuous inotropic infusions are usually initiated in intensive care units (ICU), where doses may be titrated with careful monitoring of pro-arrhythmogenic and vasodilatory effects until the patient is stabilized. Some patients may require longer periods of inotropic support, and, depending on their clinical status, may benefit from the continuity of inotropic therapy in a less intensive care setting. Our aim is to report the initial experience of a structured protocol for intravenous inotropic therapy in non-intensive care units, focusing on safety processes and end-points.</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <p>We retrospectively reviewed all consecutive patients hospitalized with HF that were discharged from ICU on an intravenous inotropic infusion in our tertiary, academic hospital from July, 2015 to December, 2017. The strategy to promote discharge to the ward on inotropic therapy was supported by an institutional protocol, which is summarized in the <xref ref-type="table" rid="t1">Table 1</xref>. Briefly, stabilized HF patients receiving a low to moderate dose of continuous intravenous inotrope (dobutamine or milrinone) for different indications in the ICU were considered for transition of care to a ward unit equipped with cardiac telemetry, except if inotrope was intended for palliation, in which case telemetry was not used. Adverse events - defined as readmission to ICU due to worsening HF, atrial arrhythmia, ventricular arrhythmia requiring inotropic dose reduction, and infection related to central intravenous access - that occurred while the patient was receiving inotropic infusion in the ward were recorded. In-hospital outcomes (death, heart transplant, left ventricular assist device - LVAD - implant or weaned off inotropes), 30-day hospital readmissions, readmission for transplant and all-cause mortality up to a censoring date on December 31<sup>st</sup>, 2017 were recorded.</p>
      <table-wrap id="t1">
        <label>Table 1</label>
        <caption>
          <title>Standard operating procedures for administration of continuous inotrope infusion in ward units</title>
        </caption>
        <table frame="hsides" rules="groups">
          <colgroup>
            <col width="100%"/>
          </colgroup>
          <thead>
            <tr>
              <th align="left">Eligibility</th>
            </tr>
          </thead>
          <tbody>
            <tr>
              <td align="left">Patients that are clinically stable for more than 24 hours on a stable dose of one continuous intravenous inotrope and able to be discharged from the ICU.</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">Central venous catheter (preferentially PICC).</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">
                <bold>Safety procedures</bold>
              </td>
            </tr>
            <tr>
              <td align="left">Discharge to a continuous cardiac telemetry ward (except if intended for palliation).</td>
            </tr>
            <tr>
              <td align="left">Medical prescription including both inotropic dose (mcg/kg/min) and rate of infusion (mL/min).</td>
            </tr>
            <tr>
              <td align="left">Maximal recommended doses for inotropes in the ward: dobutamine = 5 mcg/kg/min; milrinone = 0.5 mcg/kg/min.</td>
            </tr>
            <tr>
              <td align="left">Fixed or gradually reduced the dose of inotrope, as clinically appropriate.</td>
            </tr>
            <tr>
              <td align="left">No dose increments in the ward (patient preferentially transferred back to ICU for dose augmentation).</td>
            </tr>
            <tr>
              <td align="left">Rigorous electrolyte targets (potassium 4.0-4.5 mmol/L; magnesium &#8805; 2.0 mmol/L) and bicarbonate monitoring.</td>
            </tr>
            <tr>
              <td align="left">Systematic nursing evaluation of the patient and the administered drug according to the ward routines.</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">Daily patient assessment by the medical team.</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">
                <bold>Considerations</bold>
              </td>
            </tr>
            <tr>
              <td align="left">Exclusive intravenous access line for inotrope infusion.</td>
            </tr>
          </tbody>
        </table>
        <table-wrap-foot>
          <fn id="TFN1">
            <p>ICU: intensive care unit; PICC: peripherally inserted central catheter.</p>
          </fn>
        </table-wrap-foot>
      </table-wrap>
      <sec>
        <title>Statistical analysis</title>
        <p>Categorical variables are presented as absolute numbers and percentages, and quantitative variables as mean &#177; standard deviation or median and interquartile range, as appropriate. A Kaplan-Meier curve was plotted for survival free from heart transplant or LVAD implant during follow-up, and cumulative incidence curves were calculated for all-cause mortality and heart transplant or LVAD using competing risk analysis with the R Software, version 3.4.4 (R Project for Statistical Computing, Vienna, Austria).<xref ref-type="bibr" rid="B3">3</xref>
				</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <p>We reviewed 28 patients with HF that were discharged from the ICU to the ward on intravenous inotropes after the protocol was created. <xref ref-type="table" rid="t2">Table 2</xref> describes both patient and clinical care data during the inotropic support period. <xref ref-type="fig" rid="f1">Figure 1A</xref> depicts in-hospital outcomes of patients according to intention for inotropic support.</p>
      <table-wrap id="t2">
        <label>Table 2</label>
        <caption>
          <title>Characteristics of study patients and data pertaining the inotropic support</title>
        </caption>
        <table frame="hsides" rules="groups">
          <colgroup>
            <col width="70%"/>
            <col width="30%"/>
          </colgroup>
          <thead>
            <tr>
              <th align="left">Characteristic</th>
              <th align="center">n = 28</th>
            </tr>
          </thead>
          <tbody>
            <tr>
              <td align="left">
                <bold>Baseline Characteristics</bold>
              </td>
              <td align="center">
							</td>
            </tr>
            <tr>
              <td align="left">Age, years</td>
              <td align="center">54 &#177; 16</td>
            </tr>
            <tr>
              <td align="left">Male sex</td>
              <td align="center">20 (71.5)</td>
            </tr>
            <tr>
              <td align="left">Ischemic etiology of HF</td>
              <td align="center">16 (57)</td>
            </tr>
            <tr>
              <td align="left">Left ventricular ejection fraction, %</td>
              <td align="center">23 &#177; 7.5</td>
            </tr>
            <tr>
              <td align="left">History of atrial fibrillation</td>
              <td align="center">13 (46)</td>
            </tr>
            <tr>
              <td align="left">Implantable cardioverter defibrillator</td>
              <td align="center">13 (46)</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">Chronic kidney disease (GFR &lt; 30 mL/min/1.73 m<sup>2</sup>)</td>
              <td align="center">7 (25)</td>
            </tr>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <td align="left">
                <bold>Inotrope infusion</bold>
              </td>
              <td align="center">
							</td>
            </tr>
            <tr>
              <td align="left">
                <bold>Intravenous inotrope</bold>
              </td>
              <td align="center">
							</td>
            </tr>
            <tr>
              <td align="left">Milrinone</td>
              <td align="center">24 (86)</td>
            </tr>
            <tr>
              <td align="left">Dobutamine</td>
              <td align="center">4 (14)</td>
            </tr>
            <tr>
              <td align="left">
                <bold>Inotrope dose</bold>
              </td>
              <td align="center">
							</td>
            </tr>
            <tr>
              <td align="left">Milrinone, mcg/Kg/min</td>
              <td align="center">0.25 (0.2 - 0.34)</td>
            </tr>
            <tr>
              <td align="left">Dobutamine, mcg/Kg/min</td>
              <td align="center">5.7 (4.37 - 6.55)</td>
            </tr>
            <tr>
              <td align="left">Total duration of inotropic therapy, days</td>
              <td align="center">23.5 (13.75 - 45.5)</td>
            </tr>
            <tr>
              <td align="left">Duration of inotropic therapy at ward, days</td>
              <td align="center">10.5 (6.75 - 25)</td>
            </tr>
            <tr>
              <td align="left">
                <bold>Venous access for drug infusion</bold>
              </td>
              <td align="center">
							</td>
            </tr>
            <tr>
              <td align="left">Central venous catheter</td>
              <td align="center">4 (14)</td>
            </tr>
            <tr>
              <td align="left">Peripherally inserted central catheter</td>
              <td align="center">22 (79)</td>
            </tr>
            <tr>
              <td align="left">Peripheral venous access</td>
              <td align="center">2 (7)</td>
            </tr>
            <tr>
              <td align="left">Systolic blood pressure, mmHg<xref ref-type="table-fn" rid="TFN3">*</xref>
							</td>
              <td align="center">93 &#177; 14</td>
            </tr>
            <tr>
              <td align="left">Diastolic blood pressure, mmHg<xref ref-type="table-fn" rid="TFN3">*</xref>
							</td>
              <td align="center">59 &#177; 10</td>
            </tr>
          </tbody>
        </table>
        <table-wrap-foot>
          <fn id="TFN2">
            <p>Data expressed as number (percentage), mean &#177; standard deviation or median (interquartile range).</p>
          </fn>
          <fn id="TFN3">
            <label>*</label>
            <p>Blood pressures values at the initiation of inotropic therapy. Data from one patient not available. HF: heart failure; GFR: glomerular filtration rate.</p>
          </fn>
        </table-wrap-foot>
      </table-wrap>
      <p>
        <fig id="f1">
          <caption>
            <title>
              <italic>LVAD: left ventricular assist device.</italic>
            </title>
          </caption>
          <graphic xlink:href="1678-4170-abc-112-05-0573-90078-gf01.jpg"/></fig>
      </p>
      <p>The cohort was followed for a median of 154 days. Among those in whom inotropes were discontinued and that had hospital discharge free of heart transplant or LVAD implant (n = 8), two were readmitted for HF within 30 days. Competing outcomes for mortality during the follow-up period are demonstrated in <xref ref-type="fig" rid="f1">Figure 1B</xref>.</p>
      <p>During the period on inotropic support in the ward, nine patients returned to ICU due to worsening HF - two of those for worsening pre-existing atrial fibrillation or atrial flutter. No episodes of new atrial fibrillation or atrial flutter were observed. Six patients developed recurrent non-sustained ventricular arrhythmia, and inotropic dose was reduced; of those, four were hypokalemic (&#8804; 3.5 mmol/L) when arrhythmias were observed. One patient had a central venous catheter exit-site infection, and one had a peripherally inserted central catheter-related bloodstream infection. Seven events of protocol violation were identified: use of peripheral venous access for drug infusion (n = 2); and, increments in inotropic dose in the ward (n = 5). None of them incurred in clinical adverse events.</p>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <p>In the present report, we described our initial experience with a safety-focused protocol for the use of continuous intravenous inotropes in hospitalized patients with advanced HF outside the ICU. We demonstrated that a subset of clinically stable patients on inotropes may benefit from transition to a less intensive care setting following careful standard operating procedures, without a significant burden of adverse events. These safety measures are aligned with our institutional program for quality improvement.</p>
      <p>Current guidelines indicate that inotropes can be used in specific clinical settings, especially cardiogenic shock or bridge therapy in patients with refractory HF awaiting heart transplant or LVAD. Also, those not candidates for definitive therapies could be considered for long-term inotrope as palliation.<xref ref-type="bibr" rid="B4">4</xref> The use of intravenous inotropic agents remains controversial, as many reports have associated its utilization with unfavourable outcomes. A deleterious effect of its use on long-term mortality among patients discharged alive, however, has not been suggested by a recent European registry report.<xref ref-type="bibr" rid="B1">1</xref>
			</p>
      <p>In this study, we describe a selected population of patients with advanced HF that has not been well-documented in most studies evaluating inotropes - mostly clinically stable hospitalized patients intended for inotropic wean or bridge to definite therapies. Concerning safety outcomes, most of the arrhythmogenic events occurred in the context of electrolyte disturbances, which can be potentially avoided with careful monitoring. Considering the growing HF severity and the inotrope potential as a bridge therapy in hospitalized patients, a contemporary approach to their utilization has been to focus on the safety profile of its use while maintaining the traditional goals of therapy (the 'until' therapy), as described by Stevenson.<xref ref-type="bibr" rid="B5">5</xref> Avoidance of traditional high doses of inotropes, the administration under careful monitoring conditions and strict electrolyte correction strategies may allow broader use of these agents.</p>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclusions</title>
      <p>A contemporary, safety-focused approach to the use of low to moderate doses of intravenous inotropic agents in less resource-intensive settings may be feasible, potentially reconfiguring the use of these agents in different scenarios, ranging from bridge therapy to end-of-life palliation.</p>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="financial-disclosure">
        <p>
          <bold>Sources of Funding</bold>
        </p>
        <p>There were no external funding sources for this study.</p>
      </fn>
    </fn-group>
    <fn-group>
      <fn fn-type="other">
        <p>
          <bold>Study Association</bold>
        </p>
        <p>This study is not associated with any thesis or dissertation work.</p>
      </fn>
    </fn-group>
    <fn-group>
      <fn fn-type="other">
        <p>
          <bold>Ethics approval and consent to participate</bold>
        </p>
        <p>This article does not contain any studies with human participants or animals performed by any of the authors.</p>
      </fn>
    </fn-group>
    <ref-list>
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              <surname>Butler</surname>
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              <surname>Casey</surname>
              <given-names>DE</given-names>
              <suffix>Jr</suffix>
            </name>
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              <surname>Drazner</surname>
              <given-names>MH</given-names>
            </name>
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          <article-title>2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines</article-title>
          <source>Circulation</source>
          <year>2013</year>
          <volume>128</volume>
          <issue>16</issue>
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              <surname>Pinney</surname>
              <given-names>SP</given-names>
            </name>
            <name>
              <surname>Stevenson</surname>
              <given-names>LW</given-names>
            </name>
          </person-group>
          <article-title>Chronic inotropic therapy in the current era: old wines with new airings</article-title>
          <source>Circ Heart Fail</source>
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    </ref-list>
  </back>
  <sub-article article-type="translation" id="s1" xml:lang="pt">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Comunica&#231;&#227;o Breve</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Inotr&#243;picos Intravenosos Cont&#237;nuos em Unidades de Enfermaria: Expandindo o Tratamento Al&#233;m da Unidade de Terapia Intensiva Utilizando um Protocolo Orientado em Seguran&#231;a</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2022-7512</contrib-id>
          <name>
            <surname>Hastenteufel</surname>
            <given-names>Laura Caroline Tavares</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4207-3809</contrib-id>
          <name>
            <surname>Clausell</surname>
            <given-names>Nadine</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4413-0494</contrib-id>
          <name>
            <surname>Neyeloff</surname>
            <given-names>Jeruza Lavanholi</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-0046-836X</contrib-id>
          <name>
            <surname>Domingues</surname>
            <given-names>Fernanda Bandeira</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4932-9216</contrib-id>
          <name>
            <surname>Caballero</surname>
            <given-names>Larissa Gussatschenko</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4374-4419</contrib-id>
          <name>
            <surname>Silva</surname>
            <given-names>Eneida Rejane Rabelo da</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1523-4286</contrib-id>
          <name>
            <surname>Goldraich</surname>
            <given-names>L&#237;via Adams</given-names>
          </name>
          <xref ref-type="aff" rid="aff2"/>
          <xref ref-type="corresp" rid="c2"/>
        </contrib>
        <aff id="aff2">
          <institution content-type="original">Hospital de Cl&#237;nicas de Porto Alegre, Porto Alegre, RS - Brasil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c2"><bold>Correspond&#234;ncia: L&#237;via Adams Goldraich,</bold> Hospital de Cl&#237;nicas de Porto Alegre - Servi&#231;o de Cardiologia - Rua Ramiro Barcelos, 2350. CEP 90035-903, Porto Alegre, RS - Brasil. E-mail: <email>lgoldraich@gmail.com</email>
				</corresp>
        <fn fn-type="con">
          <p>
            <bold>Contribui&#231;&#227;o dos autores</bold>
          </p>
          <p>Concep&#231;&#227;o e desenho da pesquisa: Hastenteufel LCT, Clausell N, Domingues FB, Caballero LG, da Silva ERR, Goldraich LA; Obten&#231;&#227;o de dados: Hastenteufel LCT, Domingues FB, Caballero LG, da Silva ERR; An&#225;lise e interpreta&#231;&#227;o dos dados e An&#225;lise estat&#237;stica: Hastenteufel LCT, Neyeloff JL, Goldraich LA; Reda&#231;&#227;o do manuscrito: Hastenteufel LCT, Clausell N, Goldraich LA; Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante: Clausell N, Goldraich LA.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potencial conflito de interesses</bold>
          </p>
          <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
        </fn>
      </author-notes>
      <abstract>
        <title>Resumo</title>
        <p>Pacientes selecionados com insufici&#234;ncia card&#237;aca (IC), clinicamente est&#225;veis que necessitam de terapia inotr&#243;pica intravenosa prolongada podem se beneficiar de sua continuidade fora da unidade de terapia intensiva (UTI). Nosso objetivo foi relatar a experi&#234;ncia inicial e a seguran&#231;a de um protocolo estruturado para terapia inotr&#243;pica em unidades de terapia n&#227;o-intensiva em 28 pacientes consecutivos hospitalizados com IC que receberam alta da UTI. A utiliza&#231;&#227;o de doses inotr&#243;picas baixas a moderadas, orientadas por um processo de cuidado focado na seguran&#231;a, pode reconfigurar seu papel como terapia de transi&#231;&#227;o enquanto aguarda terapias avan&#231;adas definitivas e permite a alta precoce da UTI.</p>
      </abstract>
      <kwd-group xml:lang="pt">
        <title>Palavras-chave</title>
        <kwd>Cardiot&#244;nicos</kwd>
        <kwd>Dobutamina</kwd>
        <kwd>Insufici&#234;ncia Card&#237;aca/fisiopatologia</kwd>
        <kwd>Inotr&#243;picos</kwd>
        <kwd>Milrinone</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <sec sec-type="intro">
        <title>Introdu&#231;&#227;o</title>
        <p>Na insufici&#234;ncia card&#237;aca (IC) avan&#231;ada, pacientes com s&#237;ndrome de baixo d&#233;bito card&#237;aco podem se beneficiar de inotr&#243;picos intravenosos para proporcionar al&#237;vio sintom&#225;tico e suporte hemodin&#226;mico com diferentes prop&#243;sitos - estabiliza&#231;&#227;o do quadro agudo, ponte para terapias cir&#250;rgicas mais definitivas para doen&#231;a avan&#231;ada e palia&#231;&#227;o. Entre os pacientes admitidos com IC descompensada, cerca de 12 a 14% recebem inotr&#243;picos.<xref ref-type="bibr" rid="B1">1</xref> Entretanto, a seguran&#231;a do uso de agentes inotr&#243;picos continua sendo uma quest&#227;o preocupante.<xref ref-type="bibr" rid="B2">2</xref>
				</p>
        <p>No cen&#225;rio agudo, as infus&#245;es inotr&#243;picas cont&#237;nuas geralmente s&#227;o iniciadas em UTIs, onde as doses podem ser tituladas com monitoramento cuidadoso dos efeitos pr&#243;-arritmog&#234;nicos e vasodilatadores at&#233; que o paciente esteja estabilizado. Alguns pacientes podem necessitar de per&#237;odos mais longos de suporte inotr&#243;pico e, dependendo de seu estado cl&#237;nico, podem se beneficiar da continuidade da terapia inotr&#243;pica em um ambiente de cuidado menos intensivo.</p>
        <p>Nosso objetivo &#233; relatar a experi&#234;ncia inicial de um protocolo estruturado para terapia inotr&#243;pica intravenosa em unidades de terapia n&#227;o-intensiva, com foco em processos de seguran&#231;a e <italic>endpoints</italic>.</p>
      </sec>
      <sec sec-type="methods">
        <title>M&#233;todos</title>
        <p>Revisamos retrospectivamente todos os pacientes consecutivos hospitalizados com IC que receberam alta da UTI com infus&#227;o inotr&#243;pica intravenosa em nosso hospital terci&#225;rio universit&#225;rio, de julho de 2015 a dezembro de 2017. A estrat&#233;gia para promover a alta da terapia inotr&#243;pica na enfermaria foi apoiada por um protocolo institucional, que est&#225; resumido na <xref ref-type="table" rid="t3">Tabela 1</xref>. Resumidamente, pacientes com IC est&#225;veis que receberam uma dose baixa a moderada de inotr&#243;pico intravenoso cont&#237;nuo (dobutamina ou milrinona) para diferentes indica&#231;&#245;es na UTI foram considerados para a transi&#231;&#227;o de cuidados para uma unidade de enfermaria equipada com telemetria card&#237;aca, exceto se inotr&#243;pico fosse destinado &#224; palia&#231;&#227;o, pois nesse caso a telemetria n&#227;o era utilizada. Eventos adversos - definidos como readmiss&#227;o na UTI devido ao agravamento da IC, arritmia atrial, arritmia ventricular com necessidade de redu&#231;&#227;o da dose do inotr&#243;pico e infec&#231;&#227;o relacionada ao acesso intravenoso central - que ocorreram enquanto o paciente recebia infus&#227;o inotr&#243;pica na enfermaria foram registrados. Desfechos intrahospitalares (&#243;bito, transplante card&#237;aco, implante dispositivo de assist&#234;ncia ventricular esquerda (LVAD), implante ou desmame dos inotr&#243;picos), readmiss&#245;es hospitalares em 30 dias, readmiss&#227;o para transplante e mortalidade por todas as causas at&#233; uma data de censura em 31 de dezembro de 2017 foram registrados.</p>
        <table-wrap id="t3">
          <label>Tabela 1</label>
          <caption>
            <title>Procedimentos operacionais padro para administrao de infuso inotrpica contnua em unidades de enfermaria</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="100%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left">Elegibilidade</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Pacientes clinicamente estveis por mais de 24 horas com uma dose estvel de um inotrpico intravenoso contnuo em condies de receber alta da UTI.</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">Cateter venoso central (preferencialmente CCIP).</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">
                  <bold>Procedimentos de segurana</bold>
                </td>
              </tr>
              <tr>
                <td align="left">Alta para uma enfermaria de telemetria cardaca contnua (exceto se destinado a paliao).</td>
              </tr>
              <tr>
                <td align="left">Prescrio mdica, incluindo dose de inotrpico (mcg/kg/min) e taxa de infuso (mL/min).</td>
              </tr>
              <tr>
                <td align="left">Doses mximas recomendadas para inotrpicos na enfermaria: dobutamina = 5 mcg/kg/min; milrinona = 0,5 mcg/kg/min.</td>
              </tr>
              <tr>
                <td align="left">Dose de inotrpico fixa ou em reduo gradual, conforme clinicamente apropriado.</td>
              </tr>
              <tr>
                <td align="left">Nenhum incremento de dose na enfermaria (paciente preferencialmente transferido de volta para a UTI para aumento de dose).</td>
              </tr>
              <tr>
                <td align="left">Alvos eletrolticos rigorosos (potssio 4,0-4,5 mmol/L; magnsio &#8805; 2,0 mmol/L) e monitoramento de bicarbonato.</td>
              </tr>
              <tr>
                <td align="left">Avaliao sistemtica pela enfermagem do paciente e do medicamento administrado de acordo com as rotinas da enfermaria.</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">Avaliao diria do paciente pela equipe mdica.</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">
                  <bold>Consideraes</bold>
                </td>
              </tr>
              <tr>
                <td align="left">Linha exclusiva de acesso intravenoso para infuso inotrpica.</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN4">
              <p>UTI: unidade de terapia intensiva; CCIP: cateter central de insero perifrica.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <sec>
          <title>An&#225;lise estat&#237;stica</title>
          <p>As vari&#225;veis categ&#243;ricas s&#227;o apresentadas como n&#250;meros absolutos e porcentagens, e as vari&#225;veis quantitativas como m&#233;dia &#177; desvio padr&#227;o ou mediana e intervalo interquartil, conforme apropriado. Uma curva de Kaplan-Meier foi constru&#237;da para sobrevida livre de transplante card&#237;aco ou implante de LVAD durante o seguimento, e as curvas de incid&#234;ncia cumulativa foram calculadas para mortalidade por todas as causas e transplante card&#237;aco ou LVAD, utilizando an&#225;lise de risco concorrente com o Software R, vers&#227;o 3.4.4 (R Project para Computa&#231;&#227;o Estat&#237;stica, Viena, &#193;ustria).<xref ref-type="bibr" rid="B3">3</xref>
					</p>
        </sec>
      </sec>
      <sec sec-type="results">
        <title>Resultados</title>
        <p>Revisamos 28 pacientes com IC que receberam alta da UTI para a enfermaria com inotr&#243;picos intravenosos ap&#243;s a cria&#231;&#227;o do protocolo. A <xref ref-type="table" rid="t4">Tabela 2</xref> descreve os dados dos pacientes e de cuidados cl&#237;nicos durante o per&#237;odo de suporte inotr&#243;pico. A <xref ref-type="fig" rid="f2">Figura 1A</xref> mostra os desfechos intrahospitalares dos pacientes de acordo com a inten&#231;&#227;o para suporte inotr&#243;pico.</p>
        <table-wrap id="t4">
          <label>Tabela 2</label>
          <caption>
            <title>Caractersticas dos pacientes do estudo e dados referentes ao suporte inotrpico</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="50%"/>
              <col width="50%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left">Caracterstica</th>
                <th align="center">n = 28</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">
                  <bold>Caractersticas basais</bold>
                </td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Idade, anos</td>
                <td align="center">54 &#177; 16</td>
              </tr>
              <tr>
                <td align="left">Sexo masculino</td>
                <td align="center">20 (71,5)</td>
              </tr>
              <tr>
                <td align="left">Etiologia isqumica da IC</td>
                <td align="center">16 (57)</td>
              </tr>
              <tr>
                <td align="left">Frao de ejeo do ventrculo esquerdo,%</td>
                <td align="center">23 &#177; 7,5</td>
              </tr>
              <tr>
                <td align="left">Histrico de fibrilao atrial</td>
                <td align="center">13 (46)</td>
              </tr>
              <tr>
                <td align="left">Cardiodesfibrilador implantvel</td>
                <td align="center">13 (46)</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">Doena renal crnica (TFG &lt; 30 mL/min/1,73 m<sup>2</sup>)</td>
                <td align="center">7 (25)</td>
              </tr>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <td align="left">
                  <bold>Infuso de agente inotrpico</bold>
                </td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">
                  <bold>Agente inotrpico intravenoso</bold>
                </td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Milrinona</td>
                <td align="center">24 (86)</td>
              </tr>
              <tr>
                <td align="left">Dobutamina</td>
                <td align="center">4 (14)</td>
              </tr>
              <tr>
                <td align="left">
                  <bold>Dose de agente inotrpico</bold>
                </td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Milrinona, mcg/Kg/min</td>
                <td align="center">0,25 (0,2 - 0,34)</td>
              </tr>
              <tr>
                <td align="left">Dobutamina, mcg/Kg/min</td>
                <td align="center">5,7 (4,37 - 6,55)</td>
              </tr>
              <tr>
                <td align="left">Durao total da terapia inotrpica, dias</td>
                <td align="center">23,5 (13,75 - 45,5)</td>
              </tr>
              <tr>
                <td align="left">Durao de terapia inotrpica na enfermaria, dias</td>
                <td align="center">10,5 (6,75 - 25)</td>
              </tr>
              <tr>
                <td align="left">Acesso venoso para infuso de frmacos</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Cateter Venoso Central</td>
                <td align="center">4 (14)</td>
              </tr>
              <tr>
                <td align="left">Cateter central de insero perifrica</td>
                <td align="center">22 (79)</td>
              </tr>
              <tr>
                <td align="left">Acesso venoso perifrico</td>
                <td align="center">2 (7)</td>
              </tr>
              <tr>
                <td align="left">Presso Arterial Sistlica, mmHg<xref ref-type="table-fn" rid="TFN6">*</xref>
								</td>
                <td align="center">93 &#177; 14</td>
              </tr>
              <tr>
                <td align="left">Presso Arterial Diastlica, mmHg<xref ref-type="table-fn" rid="TFN6">*</xref>
								</td>
                <td align="center">59 &#177; 10</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN5">
              <p>Dados expressos em nmero (porcentagem), mdia &#177; desvio padro ou mediana (intervalo interquartil).</p>
            </fn>
            <fn id="TFN6">
              <label>*</label>
              <p>Valores de presso arterial no incio de terapia inotrpica. Dados de um paciente no disponvel. IC: insuficincia cardaca; TFG: taxa de filtrao glomerular.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>
          <fig id="f2">
            <caption>
              <title>
                <italic>LVAD: dispositivo de assist&#234;ncia ventricular esquerda.</italic>
              </title>
            </caption>
            <graphic xlink:href="1678-4170-abc-112-05-0573-90078-gf01-pt.jpg"/></fig>
        </p>
        <p>A coorte foi acompanhada por uma mediana de 154 dias. Entre os pacientes em quem os inotr&#243;picos foram descontinuados e que tiveram alta hospitalar livre de transplante card&#237;aco ou implante de LVAD (n = 8), dois foram readmitidos por IC em 30 dias. Desfechos competitivos para mortalidade durante o per&#237;odo de seguimento s&#227;o mostrados na <xref ref-type="fig" rid="f2">Figura 1B</xref>.</p>
        <p>Durante o per&#237;odo de suporte inotr&#243;pico na enfermaria, nove pacientes retornaram &#224; UTI devido &#224; piora da IC - dois deles por agravamento da fibrila&#231;&#227;o atrial pr&#233;-existente ou <italic>flutter</italic> atrial. N&#227;o foram observados epis&#243;dios de nova fibrila&#231;&#227;o atrial ou <italic>flutter</italic> atrial. Seis pacientes desenvolveram arritmia ventricular n&#227;o-sustentada recorrente e a dose inotr&#243;pica foi reduzida; destes, quatro estavam hipocal&#234;micos (&#8804; 3,5 mmol/L) quando as arritmias foram observadas. Um paciente teve uma infec&#231;&#227;o no local de sa&#237;da do cateter venoso central, e um teve uma infec&#231;&#227;o de corrente sangu&#237;nea relacionada ao cateter central de inser&#231;&#227;o perif&#233;rica. Sete eventos de viola&#231;&#227;o de protocolo foram identificados: uso de acesso venoso perif&#233;rico para infus&#227;o do medicamento (n = 2); e incrementos na dose inotr&#243;pica na enfermaria (n = 5). Nenhum deles incorreu em eventos cl&#237;nicos adversos.</p>
      </sec>
      <sec sec-type="discussion">
        <title>Discuss&#227;o</title>
        <p>No presente relato, descrevemos nossa experi&#234;ncia inicial com um protocolo focado na seguran&#231;a para o uso de inotr&#243;picos intravenosos cont&#237;nuos em pacientes hospitalizados com IC avan&#231;ada fora da UTI. Demonstramos que um subgrupo de pacientes clinicamente est&#225;veis em uso de inotr&#243;picos pode se beneficiar da transi&#231;&#227;o para um ambiente de tratamento menos intensivo, seguindo procedimentos operacionais-padr&#227;o cuidadosos, sem uma carga significativa de eventos adversos. Essas medidas de seguran&#231;a est&#227;o alinhadas com nosso programa institucional de melhoria da qualidade.</p>
        <p>As diretrizes atuais indicam que os inotr&#243;picos podem ser utilizados em situa&#231;&#245;es cl&#237;nicas espec&#237;ficas, especialmente choque cardiog&#234;nico ou terapia de ponte em pacientes com IC refrat&#225;ria &#224; espera de transplante card&#237;aco ou LVAD. Al&#233;m disso, aqueles que n&#227;o s&#227;o candidatos a terapias definitivas podem ser considerados para a utiliza&#231;&#227;o do agente inotr&#243;pico em longo prazo como tratamento paliativo.<xref ref-type="bibr" rid="B4">4</xref> O uso de agentes inotr&#243;picos intravenosos permanece controverso, pois muitos relatos associaram sua utiliza&#231;&#227;o a desfechos desfavor&#225;veis. Entretanto, um efeito delet&#233;rio de seu uso na mortalidade em longo prazo em pacientes que receberam alta hospitalar vivos n&#227;o foi sugerido em um recente registro europeu.<xref ref-type="bibr" rid="B1">1</xref>
				</p>
        <p>Neste estudo, descrevemos uma popula&#231;&#227;o selecionada de pacientes com IC avan&#231;ada que n&#227;o foi bem documentada na maioria dos estudos avaliando inotr&#243;picos - em sua maioria, pacientes hospitalizados clinicamente est&#225;veis destinados a desmame inotr&#243;pico ou ponte para terapias definidas. Com rela&#231;&#227;o aos resultados de seguran&#231;a, a maioria dos eventos arritmog&#234;nicos ocorreu no contexto de dist&#250;rbios eletrol&#237;ticos, que podem ser potencialmente evitados com um monitoramento cuidadoso. Considerando a crescente gravidade da IC e o potencial inotr&#243;pico como terapia de ponte em pacientes hospitalizados, uma abordagem contempor&#226;nea para sua utiliza&#231;&#227;o tem sido focar no perfil de seguran&#231;a de seu uso, e ao mesmo tempo mantendo os objetivos tradicionais da terapia (a terapia 'at&#233;'), como descrito por Stevenson.<xref ref-type="bibr" rid="B5">5</xref> Evitar o uso de altas doses tradicionais de inotr&#243;picos, a administra&#231;&#227;o sob condi&#231;&#245;es cuidadosas de monitoramento e estrat&#233;gias rigorosas de corre&#231;&#227;o de eletr&#243;litos podem permitir um uso mais amplo desses agentes.</p>
      </sec>
      <sec sec-type="conclusions">
        <title>Conclus&#245;es</title>
        <p>Uma abordagem contempor&#226;nea e com foco na seguran&#231;a para o uso de doses baixas a moderadas de agentes inotr&#243;picos intravenosos em ambientes com recursos menos intensivos pode ser vi&#225;vel, potencialmente reconfigurando o uso desses agentes em diferentes cen&#225;rios, variando de terapia de ponte a cuidados paliativos no fim de vida.</p>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="financial-disclosure">
          <p>
            <bold>Fontes de financiamento</bold>
          </p>
          <p>O presente estudo n&#227;o teve fontes de financiamento externas.</p>
        </fn>
      </fn-group>
      <fn-group>
        <fn fn-type="other">
          <p>
            <bold>Vincula&#231;&#227;o acad&#234;mica</bold>
          </p>
          <p>N&#227;o h&#225; vincula&#231;&#227;o deste estudo a programas de p&#243;s-gradua&#231;&#227;o.</p>
        </fn>
      </fn-group>
      <fn-group>
        <fn fn-type="other">
          <p>
            <bold>Aprova&#231;&#227;o &#233;tica e consentimento informado</bold>
          </p>
          <p>Este artigo n&#227;o cont&#233;m estudos com humanos ou animais realizados por nenhum dos autores.</p>
        </fn>
      </fn-group>
    </back>
  </sub-article>
</article>
