University of Groningen Rational clinical examination of the critically ill patient Hiemstra, Bart

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University of Groningen

Rational clinical examination of the critically ill patient

Hiemstra, Bart

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Rational clinical examination

of the critically ill patient

Bart Hiemstra

Rational clinical examination

of the critically ill patient

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http://books.ipskampprinting.nl/thesis/

Layout Bianca Pijl, www.pijlldesign.nl

Groningen, the Netherlands

Cover design Bianca Pijl

Printed by Ipskamp Printing

Enschede, the Netherlands

ISBN 978-94-034-1674-8 (print)

978-94-034-1673-1 (digital)

All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior written permission of the author, or when appropriate, of the publishers of the publications included in this thesis.

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Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties

De openbare verdediging zal plaatsvinden op woensdag 3 juli 2019 om 11.00 uur

door

Bart Hiemstra

geboren op 2 april 1990 te Sneek

Rational clinical examination

of the critically ill patient

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Promotores

Dr. J.C.C. van der Horst Prof. dr. A.M.G.A. de Smet Copromotor

Dr. F. Keus

Beoordelingscommissie Prof. dr. J.C. ter Maaten Prof. dr. D. van Dijk Prof. dr. D. Gommers

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Paranimfen Drs. R.J. Eck Dr. F.H. Heida

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7 Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9

Detailed statistical analysis plan of the Simple Intensive Care Studies-I The diagnostic accuracy of clinical examination for estimating cardiac index in critically ill patients: the Simple Intensive Care Studies-I Clinical examination for the prediction of mortality in the critically ill: the Simple Intensive Care Studies-I

Dopamine in critically ill patients with cardiac dysfunction:

a systematic review with meta-analysis and Trial Sequential Analysis Summary, discussion and future perspectives

Nederlandse samenvatting List of abbreviations List of publications About the author Dankwoord 9 17 33 51 67 99 145 173 209 223 225 227 229 231

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1

General introduction and thesis outline

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General introduction

Critically ill patients are admitted to the intensive care unit (ICU) regardless of the underlying pathology or referring specialism. Despite their heterogenous pathologies, all ICU patients require intensive circulatory monitoring due to a high risk of haemodynamic instability or shock, a life-threatening form of acute circulatory failure associated with cellular and tissue hypoxia due

to inadequate oxygen utilization.1,2_{Patients with shock have an increased risk of organ failure with}

long-term morbidity or even death.3

Getting insight in circulatory status and cardiac function is important for setting a diagnosis, for prognostication, and to guide decisions on interventions. Caregivers assess a patient’s circulatory status throughout physical and other clinical examinations, as early recognition and treatment of shock may prevent or reverse further deterioration (Figure 1, section A). An important determinant of oxygen delivery is cardiac output, which is the amount of blood the heart pumps through the circulation each minute. The cardiac output is regulated by various mechanisms, all with a common purpose: to maintain a constant perfusion pressure in order to provide organs and tissues with oxygen and to remove metabolic waste products. Impairment of these mechanisms lead to tissue hypoxia and circulatory shock.

Shock is divided in four subtypes, depending on different underlying pathophysiological mechanisms. Distributive shock is the most prevalent (Figure 1, section B) and is characterised by a pathologically decreased peripheral arterial vasomotor tone or intravascular volume due to vasodilation or extravasation of circulating volume. These patients typically present with a high cardiac output. Distributive shock is often caused by sepsis, yet other causes such as anaphylaxis or loss of sympathic tone (i.e., neurogenic shock) result in similar clinical presentations. Patients who suffer from shock caused by one of the other three mechanisms typically present with a low cardiac output and subsequent organ hypoperfusion (Figure 1, section C). Hypovolemic shock is caused by intravascular volume loss due to internal or external fluid loss, cardiogenic shock from cardiac diseases that diminish cardiac pump function (e.g. acute myocardial infarction or heart failure), and obstructive shock from physical obstruction of the great vessels or the heart itself (e.g. pulmonary embolism or cardiac tamponade, respectively).

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CHAPTER 1

Figure 1. Shown is an algorithm for the initial assessment of a patient in shock (Panel A), relative frequencies of the main types of shock (Panel B), and schematic representations of the four main types of shock (Panel C). The algorithm starts with the most common presentation (i.e., arterial hypotension), but hypotension is sometimes minimal or absent. CVP denotes central venous pressure, and SvO₂ mixed venous oxygen saturation. Reproduced with permission from Vincent J, De Backer D. N Engl J Med 2013;369:1726-1734, Copyright Massachusetts Medical Society.

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Thesis outline

The entire process of setting the correct diagnosis, implementing an appropriate intervention, monitoring treatment effect, and eventually improving patient prognosis in a critically ill patient is a complex chain of events. Evidence-based evaluation of such a process with complex time- dependent repeated interactions between diagnosis and treatment requires an approach that includes all three types of research: diagnostic, prognostic and a combination of intervention with prognostic research. This thesis aimed to increase the evidence base of clinical examination as a diagnostic and prognostic tool in critically ill patients.

Current evidence on clinical examination

Clinical examination is the primary test when evaluating a critically ill patient to facilitate clinical decision making and further diagnostic testing. Currently, clinical examination encompasses reviewing medical history, conducting physical examination and interpreting laboratory values, electrocardiograms, and radiography images. Clinical signs indicating circulatory failure, and biochemical and haemodynamic variables consistent with hypoperfusion are recommended

for diagnosing shock.1,2_{Despite its frequent use in routine care, the evidence base of clinical}

examination is considered `best practice’.2_{In chapter 2 we made a systematic overview of all}

studies that evaluated the diagnostic accuracy of clinical examination for diagnosing shock. Designing a cohort to study simple clinical examination findings

Observational studies are often used for diagnostic testing and prognostication. They are

considered to come closer to real-life clinical practice than randomised clinical trials (RCTs).8_On

the other hand, the credibility and reproducibily of observational studies has been questioned.9,10

Because observational studies are often published without a preregistered study protocol, it is difficult to judge if conclusions are based on a predefined research question or on a fishing

tour.11,12_{To improve transparency, journals are increasingly encouraging researchers to preregister}

their study protocol containing the rationale, hypothesis and study methods.13-15_{Prior to initaiting}

the study, we registered the study protocol of our single centre observational study, the Simple Intensive Care Studies-I (SICS-I). In chapter 3 we described the study design including the research questions, methodology, and characteristics of the patients included. The SICS-I had a focus on clinical examination of the circulation and aimed to include all acutely admitted patients. Study registration and data collection is followed by a statistical analysis phase. A multitude of

decisions are made during this fase, which has been shown to impact results and conclusions.17

Similar to study registration, journals endorsed the prepublications of statistical analysis plans (SAP) to increase reproducibility and transparency on the planned analyses. Chapter 4 presented the recommended content of SAPs for observational studies; these recommendations were adapted

from recommendations made for RCTs.18_{We based our SAP on this recommended content, also}

expecting that it may serve as an example document for future SAPs of observational studies. General introduction and thesis outline

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CHAPTER 1

The value of clinical examination

Clinical examination has a dual role since it is not only used as a diagnostic tool, but also serves as a trigger for interventions to improve patient prognosis. Clinical signs such as a low blood pressure or low urine output might reflect a poor tissue perfusion, and treatment is started to prevent vital organ damage due to hypoperfusion. A shortcoming in previous studies is that one clinical sign was associated with mortality without information of the other clinical signs or interventions. This conflicts with daily practice because the health care professional observes a broad spectrum of variables, and instigates treatments based on previous findings. In chapter 5 we studied diagnostic accuracy of a protocolised clinical examination to estimate cardiac output. Chapter 6 described which of these clinical examination variables had the strongest associations with mortality.

Interventions on haemodynamics

The prognosis of critically ill patients might improve when an intervention is started at the right trigger point. It is currently unclear which intervention (if any) is most beneficial for critically ill patients at risk of circulatory failure due to cardiac dysfunction. In a series of systematic reviews with meta-analyses, we aim to find which of the drugs used to increase cardiac pump function

(i.e. inotrope) has the most potential for improving patient outcome.19-22_{In chapter 7 of this thesis,}

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References

Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-1734.

Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine. Intensive Care Med. 2014;40(12):1795-1815. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide burden of critical illness: The intensive care over nations (ICON) audit. Lancet Respir Med. 2014;2(5):380-386.

De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789.

Kouraki K, Schneider S, Uebis R, et al. Characteristics and clinical outcome of 458 patients with acute myocardial infarction requiring mechanical ventilation. results of the BEAT registry of the ALKK-study group. Clin Res Cardiol. 2011;100(3):235-239.

Lazzeri C, Valente S, Chiostri M, Attana P, Mattesini A, Gensini GF. Mechanical ventilation in the early phase of ST elevation myocardial infarction treated with mechanical revascularization. Cardiol J. 2013;20(6):612- 617. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010;81(11):1479-1487. Dal-Re R, Ioannidis JP, Bracken MB, et al. Making prospective registration of observational research a reality. Sci Transl Med. 2014;6(224):224cm1.

Ioannidis JP. Why most published research findings are false. PLoS Med. 2005;2(8):e124.

Ioannidis JP. Why most discovered true associations are inflated. Epidemiology. 2008;19(5):640-648. Bracken MB. Preregistration of epidemiology protocols: A commentary in support. Epidemiology. 2011;22(2):135-137.

Ioannidis JP. The importance of potential studies that have not existed and registration of observational data sets. JAMA. 2012;308(6):575-576.

Loder E, Groves T, Macauley D. Registration of observational studies. BMJ. 2010;340:c950. The Lancet. Should protocols for observational research be registered? Lancet. 2010;375(9712):1. PLOS Medicine Editors. Observational studies: Getting clear about transparency. PLoS Med. 2014;11(8):e1001711.

Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: Defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207.

Ebrahim S, Sohani ZN, Montoya L, et al. Reanalyses of randomized clinical trial data. JAMA. 2014;312(10):1024-1032.

Gamble C, Krishan A, Stocken D, et al. Guidelines for the content of statistical analysis plans in clinical trials. JAMA. 2017;318(23):2337-2343.

Koster G, Wetterslev J, Gluud C, et al. Effects of levosimendan for low cardiac output syndrome in critically ill patients: Systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015;41(2):203-221.

Koster G, Bekema HJ, Wetterslev J, Gluud C, Keus F, van der Horst, I C. Milrinone for cardiac dysfunction in critically ill adult patients: A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med. 2016;42(9):1322-1335.

van der Horst I, Keus F, Hiemstra B, Koster G, Wetterslev J, Gluud C. Dopamine for cardiac dysfunction in critically ill adult patients: A systematic review with meta-analysis and trial sequential analysis. PROSPERO 2016: CRD42016042867.

van der Horst I, Keus F, Koster G, Hiemstra B, Wetterslev J, Gluud C. Dobutamine for cardiac dysfunction in critically ill adult patients: A systematic review with meta-analysis and trial sequential analysis. PROSPERO 2016 CRD42016042829. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

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Clinical examination for

diagnosing circulatory shock

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Hiemstra B, Eck RJ, Keus F, van der Horst ICC

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Abstract Purpose of review

In the acute setting of circulatory shock, physicians largely depend on clinical examination and basic laboratory values. The daily use of clinical examination for diagnostic purposes contrasts sharp with the limited number of studies. We aim to provide an overview of the diagnostic accuracy of clinical examination in estimating circulatory shock reflected by an inadequate cardiac output.

Recent findings

Recent studies showed poor correlations between cardiac output and mottling, capillary refill time or central-to-peripheral temperature gradients in univariable analyses. The accuracy of physicians to perform an educated guess of cardiac output based on clinical examination lies around 50% and the accuracy for recognizing a low cardiac output is similar. Studies that used predefined clinical profiles composed of several clinical examination signs show more reliable estimations of cardiac output with accuracies ranging from 81 up to 100%.

Summary

Single variables obtained by clinical examination should not be used when estimating cardiac output. Physician’s educated guesses of cardiac output based on unstructured clinical examination are like the ‘flip of a coin’. Structured clinical examination based on combined clinical signs shows the best accuracy. Future studies should focus on using a combination of signs in an unselected population, eventually to educate physicians in estimating cardiac output by using predefined clinical profiles.

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Introduction

Many critically ill patients suffer from circulatory shock, which places them at increased risks of

multi-organ failure, long-term morbidity and mortality.1,2_{Combinations of clinical, hemodynamic}

and biochemical variables are recommended for diagnosing shock.3,4

Daily use of clinical examination (in any patient) for diagnostic purposes contrasts with the limited number of studies, so that the level of evidence in the critically ill is considered best

practice.4 _{Much remains unknown about the value of clinical examination in diagnosing shock,}

reflected by an inadequate cardiac output (CO) or maldistribution of blood flow. More knowledge on this topic could assist physicians in the diagnostic process and guide interventions. Previous

overviews have evaluated the value of physical examination in sepsis patients,5_{cardiovascular}

patients,6_{and in haemodynamically unstable patients for predicting fluid responsiveness.}7_We

aim to provide an overview of the diagnostic test accuracy of clinical examination findings for estimating CO in critically ill patients.

Background

‘Clinical examination’ of the cardiovascular system has been performed for a long time. The first evaluations of heart rate by palpation of the arterial pulse rate date back as far as approximately

335– 280 B.C.8_{Around the second century A.D., physicians recognized the value of pulse rate in}

diagnosing diseases. Pulse quality and quantity were extensively evaluated and distinctions were

made in pulse fullness, rate, rhythm and size.9_{However, it would still take hundreds of years before}

the clinical assessment of circulatory shock ‘had evolved’ into the way as it is conducted today.

In 1941, Ebert et al.10_{elaborately described the complexity of symptoms seen in systemic and}

peripheral circulatory failure in septic shock patients. He encountered the same clinical picture that we still face today:

“(..) All the patients studied presented a similar clinical picture. They were stuporous or comatose. The rectal temperatures ranged from 36.1 to 41.3 degrees Celsius. The skin was pale and often covered with perspiration. The extremities were cold, and this finding usually preceded the fall in arterial pressure. The skin of the body was usually warm, although in terminal stages it too became cool. The radial pulse was feeble or impalpable. The pulse rate was rapid. (..)”

For years, clinical examination was considered the cornerstone for diagnosing shock. Reliance

on examination declined when Swan et al.11_{introduced pulmonary artery catheterization (PAC)}

in 1970. PAC allowed a wide range of pressure and flow-based haemodynamic measurements, including variables such as pulmonary capillary wedge pressure, systemic vascular resistance and

CO.12_{Several studies concluded that the use of PAC frequently resulted in change of therapy}

compared with clinical examination.13–18_{However, PAC remained controversial because of its}

invasiveness in the absence of any clinical benefit.19–22 _{Today, PAC has largely been replaced by}

less-invasive methods for assessment of CO, ranging from echo to pulse pressure analysis devices.23–26

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Despite these technological improvements, clinical examination still holds a prominent position

in diagnosing circulatory shock.4,27_{We aimed to provide an overview of the diagnostic accuracy}

of clinical examination for the assessment of circulatory shock measured by CO or cardiac index (CI). We only included studies that estimated CO using clinical examination based on a one-time snapshot. Physicians mostly use changes in clinical examination findings as proxy for changes in CO to guide their interventions. To evaluate the diagnostic accuracy of changes in clinical examination in relation to changes in CO was beyond the scope of this review. In this review, we were mainly interested which clinical examination findings may accommodate clinical needs, because in daily practice these snapshot measurements guide treatment decisions as triggers for interventions.

Methods

A sensitive search strategy was used to identify eligible studies. In addition, we used the snowball and citation search methods on the selected articles. We attempted to include all studies that provided results on clinical examination findings in relation to CO. We excluded prognostic studies. We separated studies that evaluated univariable associations from studies that used multivariable analyses. Varying statistical indices for describing diagnostic test accuracy as well as a varying prevalence of low CO were encountered, limiting interstudy comparison. Whenever available, we used likelihood ratios as the preferred modality to describe diagnostic accuracy. Likelihood ratios may provide valuable information on disease probability in an individual and do

not change with pretest probability (i.e. the prevalence of disease).28–30_{We calculated sensitivity,}

specificity, predictive values and likelihood ratios of clinical examination for the detection of low CO whenever possible.

Results

Our search resulted in 8,128 hits of which 28 publications were selected. An additional six publications were identified through snowballing. After selection, we included 34 publications in this overview.

Univariable studies

Thirteen studies evaluated univariable associations of clinical examination variables with CO,

including skin temperature or temperature gradients (n=8),31–38_{capillary refill time (CRT; n=1),}39

temperature gradient and CRT (n=1),40_{mottling (n=1),}41_{heart rate and mean arterial pressure}

(n=1),42_{and central venous pressure (n=1; Table 1).}43_{The method used for measuring CO varied,}

including e.g. thermodilution with the PAC or Doppler wave with transesophageal or transthoracic echocardiography (Table 1).

Circulatory shock may lead to compensatory vasoconstriction of non-vital, peripheral tissues such as the skin. Peripheral perfusion can easily be evaluated by measurement of skin temperature, CRT, and degree of skin mottling. Two studies demonstrated that a subjectively cool skin

temperature was associated with a lower CO.31,32_{Studies evaluating the correlation between}

objective temperature measurements and CO showed conflicting results; some observed

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moderate correlations,33,35,40,_{whereas most observed no correlation.}34–38_{Skin temperature}

measurement methods differ widely and are likely influenced by several factors: age, ambient temperature, hypothermia, peripheral vascular disease, vasopressors, pain, and anxiety have all

been proposed as influencing circumstances.44,45_{This may explain the conflicting results and may}

limit its usefulness for estimating CO in clinical practice. Several studies have emphasized the

prognostic value of prolonged CRT and mottling of the skin,39,41,46–49_{but only three studies have}

evaluated their associations with CO and found no relevant correlations.39–41

Prospective studies on systemic haemodynamic variables showed that heart rate, mean arterial

pressure and central venous pressure were not directly correlated to CO.42,43,50_{Only during}

episodes of deep hypotension, one study observed a moderate correlation between mean

arterial pressure and CO.42_{These systemic haemodynamic variables seem to be poor indicators of}

CO, which supports the common conception that low blood pressure is a late sign of circulatory

shock and should not be relied on for early diagnosis.4,51

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Table 1.

Pr

ediction of c

ar

diac output using a single v

ariable * = Repeat ed measur ements in each patient. # = same study population. Abbr eviations: Temp , t emper atur e [°C ); CI, car diac index [L ∙ min -1 ∙ m -2]; PA C, pulmonar y ar ter y cathet er ; C O , car

diac output [L ∙ min

-1]; Δ Tp - a, peripher al-t o-ambient t emper atur e gr adient [°C ]; Δ Tc-p , c entr al-t o-peripher al t emper atur e gr adient [°C ]; CR T, c apillar y r

efill time (s); TEE

, tr ansoesophageal echoc ar diogr aphy ; T TE , tr ansthor acic echoc ar diogr aphy ; HR, hear t r at e [beats/min ut e]; MAP , mean ar terial pr essur e [mmHg]. Ta bl e 1. P re di ct io n of ca rdi ac o ut put us ing a singl e va ria bl e Aut ho r; ye ar Pa tie nts P op ul at ion Va ria bl es of in te re st M ea su re m en t me th od Re su lts Non -s igni fica nt Si gni fic ant Peri ph era l t em pera tu re Ka pla n e t a l. 31; 20 01 264 * Sev er e inj ury a nd se pt ic s ho ck, v asc ula r di se ase a nd va rio us Te mp , s ubj ec tiv e: foot (‘ co ol ’ or ‘w ar m ’) PA C, te chn iq ue n ot m ent io ne d - 'C oo l' : C I = 2 .9 ± 1. 2 'W ar m ': C I = 4 .3 ± 1. 2 Sc he y e t a l. 32; 20 09 10 * Po st ca rdia c s urg ery Te mp , s ubj ec tiv e: foot : ( ‘co ol ’ or ‘c oo l-w ar m’ o r ’ w ar m’ ) Te mp , o bj ec tiv e of fo ot PA C, t he rm od ilut io n Tskin , o bje ct iv e: r =. 11 'C oo l' : C O = 3. 71 'C ool -w ar m ': C O = 4. 83 'W ar m ' : C O = 5 .12 Jo ly e t a l. 33; 1969 100 Cir cul ato ry sho ck Te mp , o bj ec tiv e: toe ΔT: to e - a m bie nt ( ΔTp -a) Ind ica to r d ilut io n te chn iq ue - Tskin ob je ctiv e: r= .7 1 ΔTp -a: r =. 73 W oo ds e t a l. 34; 1 987 26 * Cir cul ato ry sho ck ΔT : c en tr al - to e ( ΔTc -p) PA C, t he rm od ilut io n ΔTc -p: no co rre la tio n Vi nc ent e t a l. 35; 1 988 15 * Ca rd io ge nic a nd se pt ic sh oc k ΔT: to e - a m bie nt ( ΔTp -a ) PA C, t he rm od ilut io n ΔTp -a in se ptic sh oc k: no co rre la tio n ΔTp -a in car di og en ic s ho ck : r =. 63 Ba ile y e t a l. 40; 19 90 # 40 * Po st ca rdia c s urg ery ΔT: ce nt ra l to e ( ΔTc -p) PA C, t he rm od ilut io n ΔTc -p da y o f o pe ra tio n: no co rr el ati on ΔTc -p po st -o pe ra tiv e da y 1 : r= -.6 0 So mme rs e t a l. 36; 1995 21 * Po st ca rdia c s urg ery Tskin , o bje ct iv e: ax ill ary , g ro in, kne e, a nkl e, to e PA C, t he rm od ilut io n Tskin , o bj ec tiv e: no co rre la tio n i n a ny si te - Bo er m a e t al . 37; 2 008 35 Se psi s a nd se pt ic sho ck ΔT : c en tr al - fo ot (Δ Tc -p) TEE , D op pl er w av e ΔTc -p : r =-.1 5 - Bo ur cie r e t a l. 38; 2016 103 * Se psi s a nd se pt ic sho ck ΔT: to e - a m bie nt ( ΔTp -a) TT E, t ec hn iq ue no t m ent io ne d ΔTp -a : no co rre la tio n - Ca pi lla ry re fil l t im e Ba ile y e t a l. 40; 19 90 # 40 * Po st ca rdia c s urg ery CR T: sit e n ot m en tio ne d PA C, t he rm od ilut io n CR T: no co rr ela tio n - Ai t-O uf el la e t al . 39; 2014 * 59 Se ptic sh oc k CR T: in de x ﬁ ng er Fl oT rac TM, a rte ria l pr es sur e wa ve fo rm a na ly sis CRT: n o c orre la tio n - Ski n m ot tli ng Ai t-O uf el la e t a l. 41; 2011 60 Se ptic sh oc k M ott ling sc ore : k nee TT E, Do pp le r w av e M ott ling sc ore : n o co rr el ati on - Sys te m ic ha em od yn am ic var iab le s W o e t a l. 42; 1993 256 * Se ve re inj ury a nd cri tic ally -ill po st -ope ra tiv e HR , MA P PA C, t he rm od ilut io n HR : r =. 27, r 2=. 07, MA P: r= -. 01, r 2= . 0001, M AP d urin g se ve re h yp ote nsi on : r= .50 , r 2=. 25 Ku nt sc he r e t a l. 43; 2006 16 * M aj or b ur ns Ce ntr al ve no us pre ss ur e Th er m al dy e do ubl e in dic ato r d ilut io n - Ce ntr al ve no us pre ss ur e: r= .4 0 * = Re pe ate d m ea sur em ents in e ac h pa tie nt. # = sa m e st udy po pu la tio n. A bb re via tio ns : T em p, te m pe ra tu re (˚ C); CI , ca rd iac in de x ( L∙m in -1∙m -2); P AC , p ul m on ar y a rt er y c at he te r; C O, ca rd ia c o ut pu t ( L∙m in -1); ΔTp -a , pe riph er al -to -a m bi en t te m pe ra tur e gra di ent (˚C ); ΔTc -p , c en tr al -to -pe riph era l te m pe ra ture g ra die nt (˚C ); CR T, ca pil la ry re fil l t im e (s ); TE E, tra nso eso pha ge al e ch oc ard io gra phy ; T TE , tr an st ho raci c e ch ocar di og rap hy ; H R, h ea rt ra te (b ea ts/ m in ut e) ; M AP , m ea n a rte ria l pre ss ur e (mmHg ).

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Multivariable studies

Twenty-one studies evaluated multivariable associations of clinical variables with CO. Due to the differing methods of estimating CO, we subdivided our results into studies that evaluated the

capacity of physicians to estimate CO (n = 17; Table 2)13–18,52–62_{and studies that constructed clinical}

profiles based on multiple variables (n = 3) or a multivariable model (n = 1) to correlate clinical

examination findings with CO (Table 3).63–66_{Furthermore, we could calculate the diagnostic test}

accuracy for physician’s estimation of low CO in nine studies (Table 2). Physician’s capacity to estimate CO based on clinical examination

Seventeen studies evaluated the accuracy of physician’s estimates or ‘educated guesses’ of CO as compared to objectively measured CO. Estimates were based on clinical examination, with or without knowledge of medical history, biochemical values and/or radiological imaging. (Table 2). Some studies used a categorical variable for CO estimates (e.g., ‘low’, ‘normal’ or ‘high’), while others

used a continuous scale (e.g., 1 - 12 liters per minute).15,17,58_{Physician’s estimates were correct in}

42% to 62% of the time.13–18,52–57,59–62_{Moderate to reasonable correlations and a high percentage}

error were found when physician’s estimates of continuous CO were compared to objectively

measured CO.15,16,58_{Moderate to very poor agreements were found in studies that used weighted}

κ statistics to address agreement occurring by chance.56,62,67,68_{In addition, two studies reported}

that in 21% and 26% CO estimations were completely disparate (an estimated high CO when the

objective CO was low, or vice versa).55,67

Nine studies provided enough data for calculation of the diagnostic accuracy of physician’s

estimates for detecting low CO. The overall results appeared disappointing (Table 2).13,14,16,17,52,54,56,60,61

Furthermore, two studies concluded that physicians more frequently overestimated (31-33%)

rather than underestimated (18-23%) CO,14,53_{implicating that physicians were more prone to miss}

an insufficient CO. Perel et al.58_{found the opposite when physicians were asked to estimate CO}

on a continuous scale.

These results suggest that physicians are not very capable to subjectively estimate CO based on clinical examination. The widely varying diagnostic accuracies are probably the result of different populations or cut-offs for a low CO, but overall it seems that physician’s estimates are

‘an inaccurate diagnostic test’. This in accordance with two studies of Saugel et al.,68,69_{which both}

demonstrate the incapability of physicians to reliably assess volume status using simple clinical signs. Furthermore, five out of six studies concluded that predictions of senior staff members were

equally bad as those of residents or fellows.13,18,57,58,61,70_{Finally, one study found that the accuracy of}

estimates was unrelated to the level of confidence physicians had in their assessment.70

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24 Table 2. Physician ’s c apacit y t o estimat e C O based on clinic al ex amination * = R epeat ed measur

ements in each patient. # = o

verlapping study populations

. Abbr

eviations: 95% CI, 95% c

onfidenc

e int

er

vals; ICU, int

ensiv e c ar e unit; P AC, pulmonar y ar ter y c athet er ; CI, c ar

diac index [L ∙ min

ut e∙m 2]; C O , c ar

diac output [L/min]; EC

G, electr oc ar diogr aphy ; P AOP , pulmonar y ar ter y oc clusion pr essur e [mmHg]; SVRI, syst emic v ascular r esistanc e index [dynes ∙ sec ∙ cm 5 ∙ min 2]; TEE , tr ansesophageal echoc ar diogr aphy ; LiDC O , lithium dilution c ar diac output; P iC CO , pulse c ont our c ar diac output; S ens , sensitivit y; Spec , specificit y; PPV , positiv e pr edictiv e v alue; NPV , negativ e pr edictiv e v alue; LR+, positiv e lik elihood r atio; LR –, negativ e lik elihood r atio Ta bl e 2. Ph ysi cia n’ s c ap ac ity to e st im at e C O ba se d on cli ni ca l e xa m in at io n Aut ho r; ye ar Pa tie nts Se tti ng Va ria bl es of in te re st M ea su re m en t me th od Re su lts Cla ss ific at io n Es tim ati on b as ed o n Es tim ati on Di agn os tic ac cur ac y f or lo w C O (9 5% CI ) Con nor s e t a l. 13; 19 83 62 * ICU CI c at eg or ica l: <2. 5; 2. 5-3. 5; > 3. 5 Clin ica l a ss es sm en t, la b, X -Ra y PA C, th er m od ilu tion 44% co rr ec t e st im at io n Se ns 58% (45 -68 %) ; S pe c 60% (48 -71 % ) PPV 5 8% (4 9-65% ) ; N PV 6 0% (5 2-67% ) LR + 1. 43 (1. 02 -2. 00 ) ; LR – 0. 71 (0. 51 -0 .98) Ei se nb er g et a l. 14; 19 84 97 ICU CO ca teg or ica l: <4. 5; 4. 5-7. 5; > 7. 5 Not d es cr ib ed PA C, th er m od ilu tion 51% co rr ec t e st im at io n Se ns 71% (54 -85 %) ; S pe c 56% (43 -69 % ) PPV 4 8% (39 -57 %) ; N PV 7 8% (66 -86 %) LR + 1. 64 (1. 15 -2. 33 ) ; LR – 0. 51 (0. 29 -0 .89 ) Tuc hs ch m idt e t al . 15; 198 7 35 ICU CO co nt inuo us Cl in ica l a sse ssm en t, X -Ra y PA C, th er m od ilu tion r= .7 2 - Con nor s e t a l. 59 19 87 69 ICU CI c at eg or ica l: <2. 5; 2. 5-3. 5; > 3. 5 Clin ica l a ss es sm en t, la b, X -Ra y, E CG - Con nor s e t a l. 17; 19 90 46 1 ICU CI di cho to m ous : <2. 2; ≥ 2. 2 CI co nt inuo us Clin ica l a ss es sm en t, la b, X -Ra y, E CG PA C, th er m od ilu tion 64% co rr ec t e st im at io n Ab sol ut e mea n di ffe re nc e i n CI = 1. 0 ± 0. 9 Se ns 49% (40 -57 %) ; S pe c 70% (65 -75 % ) PPV 4 3% (38 -49 %) ; N PV 7 4% (71 -77 %) LR+ 1. 62 (1. 28 -2. 05 ) ; LR – 0. 73 (0. 62 -0 .87 ) Ce lor ia e t a l. 16; 19 90 # 11 4 Su rg ica l IC U CO ca teg or ica l: <4; 4 -8; > 8 Clin ica l a ss es sm en t, la b, X -Ra y PA C, th er m od ilu tion 51% co rr ect e st im at ion r= .4 7 Se ns 67% (30 -93 %) ; S pe c 80% (71 -87 % ) PPV 2 2% (14 -34 %) ; N PV 9 7% (92 -99 %) LR+ 3. 33 (1. 83 -6. 07 ) ; LR – 0. 42 (0. 16 -1 .05 ) St ei ng ru b e t a l. 60; 19 91 # 15 2 Sur gi ca l a nd m ed ica l IC U CO ca teg or ica l: <4; 4 -8; > 8 Clin ica l a ss es sm en t, l ab , X -Ra y PA C, th er m odi lut io n 51% co rr ec t e st im at io n Se ns 54% (37 -70 %) ; S pe c 73% (63 -81 % ) PPV 4 0% (31 -51 %) ; N PV 8 2% (76 -87 %) LR+ 1. 96 (1. 29 -2. 98 ) ; LR – 0. 64 (0. 44 -0 .91 ) M im oz e t a l. 18; 19 94 11 2 ICU Co m bi na tio ns of C I, PA OP , S VR I Clin ica l a ss es sm en t, la b, X -Ra y, e ch oc ar di og ra ph y PA C, th er m od ilu tio n 56% co rr ec t e st im at io n - St au di ng er e t a l. 61; 19 98 14 9 ICU CI c at eg or ica l: <2. 0; 2. 0-4. 0; > 4. 0 Clin ica l a ss es sm en t, m ed ica l hi st or y, la b, X -Ra y PA C, th er m od ilu tion 62% co rr ec t e st im at io n - Rod rig ue z e t a l. 55; 20 00 33 ED + re sp ira tor y di st re ss o r hy pot en sion CI c at eg or ica l: <2. 6; 2. 6-4. 0; > 4. 0. Clin ica l a ss es sm en t, m ed ica l hi st or y, la b, X -Ra y, E CG TE E, D op pl er wa ve κ1 = -0. 04 (9 5% C I -0. 31 - 0. 24) κ2 = 0. 07 (95% C I -0. 17 - 0. 31) - Lint on e t a l. 52; 20 02 50 Po st car di ac su rg er y CI c at eg or ica l: <1. 9; 1. 9-3. 5; > 3. 5 Not d es cr ib ed LiD CO TM, i ndi ca to r-dilu tio n 54% co rr ec t e st im at io n Se ns 42% (15 -72% ) ; S pe c 74% (57 -87 % ) PPV 3 3% (1 8-54% ) ; N PV 8 0% (7 1-87% ) LR+ 1. 58 (0 .6 7-3. 72 ) ; LR – 0. 79 (0. 47 -1 .32) Ire gu i e t a l. 53; 20 03 10 5 ICU CI c at eg or ica l: <2. 5; 2. 5-4. 5; > 4. 5 Clin ica l a ss es sm en t, la b, X -Ra y TE E, D op pl er wa ve 44% co rr ec t e st im at io n - Ve al e et a l. 54; 20 05 68 ICU CI ca teg or ica l: <2. 5; 2. 5-4. 2; > 4. 5 Not d es cr ib ed Bi oZ C O mo ni to r TM, Im pe da nc e c ar di og ra phy 42% co rr ec t e st im at io n Se ns 22 % ( 6-48 % ) ; S pe c 66 % ( 51 -79 % ) PPV 19 % (8 -38 % ) ; N PV 7 0% (63 -76 %) LR+ 0 .65 (0. 25 -1 .68 ) ; LR – 1 .18 (0. 86 -1. 62) Rod rig ue z e t al . 67;200 6 31 ED + en dot ra ch ea l int uba tio n CI c at eg or ica l: ra ng es n ot sp ec ifi ed Clin ica l a ss es sm en t, m ed ica l hi st or y, la b, X -Ra y TE E, D op pl er wa ve κ = 0. 57 (95 % C I 0. 36 - 0. 77) - Nowa k et a l. 56; 20 11 38 ED + re sp ira tor y di st re ss CO ca teg or ica l <4. 0; 4. 0-8. 0; > 8. 0 Clin ica l a ss es sm en t, m ed ica l hi st ory Ne xfi n TM, a rt eri al pr es su re wa ve for m an al ys is 50% co rr ec t e st im at io n κ = -0. 02 ( 95 % C I -0. 25 - 0. 20) Se ns 33% (4 -7 8% ) ; S pe c 63% (44 -79 % ) PP V 1 4% (5 -36 % ) ; N PV 83% (7 3-90% ) LR+ 0. 89 ( 0. 26 -3. 00 ) ; LR – 1. 07 (0. 57 -2 .00) Dua n e t a l. 57 20 14 13 2 ICU CI ca teg or ica l: <3; 3 -5; > 5 Not d es cr ib ed Pi CCO TM, t he rm od ilu tion 50 % co rr ec t e st im at ion - Pe re l e t a l. 58; 2 016 20 6* ICU CO co nt inuo us Cl in ica l a sse ssm en t Pi CCO TM, t he rm odi lut io n Pe rc en ta ge e rr or = 6 6% Ab sol ut e m ea n d iff er en ce in -

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25 Table 2. Physician ’s c apacit y t o estimat e C O based on clinic al ex amination * = R epeat ed measur

ements in each patient. # = o

verlapping study populations

. Abbr

eviations: 95% CI, 95% c

onfidenc

e int

er

vals; ICU, int

ensiv e c ar e unit; P AC, pulmonar y ar ter y c athet er ; CI, c ar

ut e∙m 2]; C O , c ar

diac output [L/min]; EC

G, electr oc ar diogr aphy ; P AOP , pulmonar y ar ter y oc clusion pr essur e [mmHg]; SVRI, syst emic v ascular r esistanc e index [dynes ∙ sec ∙ cm 5 ∙ min 2]; TEE , tr ansesophageal echoc ar diogr aphy ; LiDC O , lithium dilution c ar diac output; P iC CO , pulse c ont our c ar diac output; S ens , sensitivit y; Spec , specificit y; PPV , positiv e pr edictiv e v alue; NPV , negativ e pr edictiv e v alue; LR+, positiv e lik elihood r atio; LR –, negativ e lik elihood r atio

Several important limitations apply. Many studies did not elaborate their methods of clinical examination in terms of variables used and definitions employed, leaving variability at the physician’s discretion so that these studies cannot be reproduced. PAC was used in most studies, but only in selected patients who failed to respond to initial therapy or in whom clinical examination alone was deemed insufficient, so that evaluation of the accuracy of clinically estimated CO will be biased by definition. Likewise, many other studies also used convenience samples which hampers generalisability of their results. Clinical examination should be performed in a standardised fashion, according to a protocol, to maximize inter-observer agreement and generalisability.

Combined signs of clinical examination for estimation of CO

Three studies have compared predefined clinical profiles based upon clinical examination with

objectively measured CI (Table 3). Forrester et al.64_{found a good agreement in patients with acute}

myocardial infarction (AMI). In their study, 75% of patients with low CI and 96% of patients with very low CI had clinical signs of peripheral hypoperfusion, such as decreased skin temperature, confusion or oliguria in conjunction with either arterial hypotension or tachycardia. Ramo et

al.63_{observed 100% correct estimation of low CI when patients with AMI had overt signs of}

pulmonary oedema or signs of cardiogenic shock. In their study, clinical signs of overt pulmonary oedema were defined by rales or a third heart sound gallop rhythm and cardiogenic shock was diagnosed by the presence of a systolic blood pressure < 90 mmHg, oliguria, cold extremities, and disorientation. These findings suggest that physicians can diagnose cardiogenic shock in patients with AMI using clinical examination. Accurate estimation of CO for diagnosing shock in all critically ill patients based on clinical examination might appear much more difficult due to

large inter-individual differences. Grissom et al.65_{combined CRT, mottling and skin temperature to}

predict CI in an unselected cohort of patients with acute lung injury. Presence of all three physical signs had a high specificity (98%) but a low sensitivity (12%) for diagnosing shock, suggesting that these three signs accurately rule in, but inaccurately rule out circulatory shock. Varying types

of shock are probably associated with varying clinical signs,71_{so that a ‘one size fits all’ approach}

seems inappropriate. Roughly one-third of all patients with circulatory shock suffer from a low

CO, whereas two-thirds have distributive shock with associated high CO.1,71_{Especially in the latter,}

clinical examination may indicate inadequate circulation regardless of the height of CO and it is difficult to establish how much CO is sufficient for each individual patient.

Predicting CO using a multivariable model

One study used multivariable regression analyses to estimate CO based on heart rate, respiratory

rate, mean arterial pressure, and central temperature (Table 3).66_{These multivariable results}

confirm that systemic haemodynamic variables do not correspond well with CO. Future diagnostic studies of CO should therefore incorporate all clinical and hemodynamic variables in a multivariable model.

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26

Table 3.

Combined signs of clinic

al ex

amination for estimation of C

O

* = R

epeat

ed measur

ements in each patient. Abbr

eviations: CI, c

ar

-1 ∙ m -2]; HF , hear t f ailur e; P AC, pulmonar y ar ter y c athet er ; C O , c ar

diac output [L ∙ min

-1]; S ens , sensitivit y; Spec , specificit y; PPV , positiv e pr edictiv e v alue; NPV , negativ e pr edictiv e v alue; LR+, positiv e lik elihood r atio; LR –, negativ e lik elihood r atio . Ta bl e 3. Com bi ne d sig ns of cl in ical e xam in ati on for e sti m ati on of CO Aut ho r, y ea r Pa tie nts Pop ul at ion Va ria bl es of in te re st CO -me as ur eme nt Re su lts Clin ica l p ro file Clin ica l p ro file bas ed o n Com bi ne d cl in ica l p rof ile s Ra mo et a l. 63; 19 70 98 Ac ut e m yoc ar di al in fa rc tio n I (n or ma l C I): n o s ign s o f HF II (n or ma l C I): m ild to m od er at e HF III (low C I): ove rt p ul m on ar y oed ema IV (low C I): ca rd iog en ic s hoc k M ea n a rt eri al p re ss ure , c ool ex tr em iti es , ur ine o ut put , m ent al st at us, thi rd he ar t s ound g allo p rh yt hm , ra le s PA C, indi ca to r-di lut io n te chni que I (n or ma l C I): 23 of 45 (5 1% ) II (n or ma l C I): 1 9 o f 30 (6 3% ) III (low C I): 10 o f 10 (1 00 % ) IV (l ow C I): 1 3 of 13 (1 00 % ) For re st er e t al . 64; 197 7 20 0 Ac ut e m yoc ar di al in fa rc tio n I (n or ma l CI ): n o pu lm on ar y con ge st ion or pe riphe ra l hy po pe rfus io n II (no rm al CI ): pu lm on ar y c on ge st ion on ly III (low C I): hy po pe rfus io n o nl y IV (low C I): b oth He ar t r at e, b lo od p re ss ur e, cool ex tr em iti es , ur ine o ut put , m ent al sta tu s PA C, th er m od ilu tion Ove ra ll: 8 1% co rr ect es tima tio ns of C I I & II ( no rm al C I): 84 o f 95 (88 % ) III & IV (l ow C I): 76 o f 1 05 ( 72% ) Gr iss om e t al . 65; 200 9 40 5 Ac ut e l ung inj ur y I: A ll t hr ee clin ica l s ig ns a be rr an t II: A ny o ne cl ini ca l s ig n a be rr ant Ca pilla ry re fill t im e, k ne e m ottl in g, cool e xt re m iti es PA C, th er m od ilu tion 92 % co rr ec t e st im at ion s of C I in cla ss I: Se ns 1 2% (3 -2 8% ) ; S pe c 98 % (97 -99 % ) PPV 4 0% (17 -69 %) ; N PV 93 % (92 -93 %) LR + 7. 52 (2. 23 -25.3 ) ; LR – 0. 89 (0. 79 -1 .01 ) 75 % co rre ct e st im at io ns o f C I in cla ss II: Se ns 5 2% (34 -69% ) ; S pe c 7 8% (73 -82 % ) PPV 17 % (12 -23 %) ; N PV 95 % (93 -96 %) LR + 2. 31 (1. 58 -3. 38 ) ; LR – 0. 62 (0. 44 -0 .89 ) M ul tiv ar ia bl e an al ys is Sa ss e et a l. 66; 19 96 23 * ICU pa tie nt s CO co nt inuo us He art ra te , r es pi ra tor y r at e, m ea n art eri al p re ss ure, te m pe ra tu re PA C, th er m od ilu tion He art ra te : R 2 =. 05 Re sp ira tor y r at e: R 2 =. 14 M ea n a rt eri al p re ss ure : R 2 = . 03 * = Re pe at ed m ea su re m en ts in e ac h pa tie nt . A bb re vi at ion s: CI , c ar di ac ind ex ( L∙ mi n -1∙m -2); H F, h ea rt fa ilu re ; P AC, pul m ona ry a rt er y c at he te r; CO , c ard ia c o ut put (L ∙mi n -1); Se ns , s en sit ivi ty ; S pe c, sp ec ifi cit y; P PV , pos iti ve p re di ct ive va lu e; N PV , n eg at ive p re di ct ive va lu e; LR +, p os iti ve li ke lih ood ra tio ; L R– , n eg at ive li ke lih ood ra tio.

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27

Conclusion

Clinical examination findings are poorly associated with CO in single-variable and multivariable analyses. Physicians seem to be insufficiently capable to estimate CO or recognise a low CO using their clinical examination. The most promising results were found when CO was estimated by using predefined profiles composed of combined clinical examination signs. However, most studies were conducted in highly selected populations and the details of estimations were not specified. On the basis of current evidence, using clinical examination to diagnose CO can, to our opinion, not be considered best practice. Future studies on this topic should be conducted in a representative population, use standardised clinical examination and use appropriate statistical indices of diagnostic accuracy. Ultimately, these results should guide education of physicians to estimate CO using predefined clinical profiles.

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Clinical examination, critical care

ultrasonography and outcomes in the

critically ill: cohort profile of the

Simple Intensive Care Studies-I

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Hiemstra B, Eck RJ, Koster, G, Wetterslev J, Perner A, Pettilä V, Snieder H, Hummel YM, Wiersema R, de Smet AMGA, Keus F, van der Horst ICC, SICS Study Group

University of Groningen Rational clinical examination of the critically ill patient Hiemstra, Bart