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[ Contemporary Reviews in Critical Care Medicine ] 56

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7
Management of Refractory Vasodilatory 61
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8
9
Q1 Q2
Shock 63
64
10 65
Q17 Jacob C. Jentzer, MD; Saraschandra Vallabhajosyula, MBBS; Ashish K. Khanna, MD; Lakhmir S. Chawla, MD;
11 66
Q3 Laurence W. Busse, MD; and Kianoush B. Kashani, MD
12 67
13 68
14 69
15 Refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate 70
16 hemodynamic response to high doses of vasopressor medications. Approximately 7% of 71
17 critically ill patients will develop refractory shock, with short-term mortality exceeding 50%. 72
18 Refractory vasodilatory shock develops from uncontrolled vasodilation and vascular hypores- 73
19 ponsiveness to endogenous vasoconstrictors, causing failure of physiologic vasoregulatory 74
20 mechanisms. Standard approaches to the initial management of shock include fluid resuscita- 75
21 tion and initiation of norepinephrine. When these measures are inadequate to restore BP, 76
22 vasopressin or epinephrine can be added. Few randomized studies exist to guide clinical 77
23 78
management and hemodynamic stabilization in patients who do not respond to this standard
24 79
approach. Adjunctive therapies, such as hydrocortisone, thiamine, and ascorbic acid, may
25 80
increase BP in severe shock and should be considered when combination vasopressor therapy is
26 81
needed. Novel vasopressor agents, such as synthetic human angiotensin II, can increase BP
27 82
28 and reduce the need for high doses of catecholamine vasopressors in severe or refractory 83
29 vasodilatory shock. Few effective rescue therapies exist for established refractory shock, which 84
30 emphasizes the importance of aggressive intervention before refractory shock develops, 85
31 including the earlier initiation of rational combination vasopressor therapy. The present review 86
32 discusses the diagnosis and management of refractory shock to offer guidance for management 87
33 of this important clinical problem and to provide a framework for future research. 88
34 CHEST 2018; -(-):--- 89
35 90
36 KEY WORDS: angiotensin II; hypotension; refractory shock; shock; vasopressin; vasopressor therapy Q6 91
37 92
38 93
Circulatory shock is the most serious triggering cause and restoring adequate organ Q7
39 94
40
manifestation of cardiovascular failure perfusion by using fluid resuscitation and 95
41 encountered in critically ill patients and is vasoactive medications, as necessary.1 96
42 characterized by hypotension and tissue Circulatory shock develops in approximately 97
43 hypoperfusion that can lead to inadequate 33% of critically ill patients worldwide.2,3 98
44 cellular oxygen utilization and organ failure.1 Vasodilatory or distributive shock is the most 99
45 Management of shock involves correcting the common form of shock and will typically 100
46 101
47 102
48 103
ABBREVIATIONS: iNOS = inducible nitric oxide synthase; MAP = Diego, CA; and Division of Pulmonary, Allergy, Critical Care and
49 mean arterial pressure; NO = nitric oxide; NOS = nitric oxide synthase; Sleep Medicine (Dr Busse), Emory University School of Medicine, 104
50 RCT = randomized controlled trial Atlanta, GA. 105
51 AFFILIATIONS: From the Department of Cardiovascular Medicine CORRESPONDENCE TO: Jacob C. Jentzer, MD, Department of 106
(Drs Jentzer and Vallabhajosyula), Division of Pulmonary and Cardiovascular Medicine, Mayo Clinic, 200 First St SW, Rochester,
52 107
Critical Care Medicine (Drs Jentzer and Kashani), and Division of MN 55905; e-mail: jentzer.jacob@mayo.edu Q5
53 Q4 Nephrology and Hypertension (Dr Kashani), Mayo Clinic, Roches- Copyright Ó 2018 American College of Chest Physicians. Published by 108
54 ter, MN; Anesthesiology Institute (Dr Khanna), Center for Critical Elsevier Inc. All rights reserved. 109
Care and Department of Outcomes Research, Cleveland Clinic,
55 DOI: https://doi.org/10.1016/j.chest.2017.12.021 110
Cleveland, OH; La Jolla Pharmaceutical Company (Dr Chawla), San

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111 require the use of vasopressor agents to restore adequate norepinephrine equivalents at baseline.24,26 166
112 vascular tone.1,4 Despite recent advances in therapy, the Norepinephrine-equivalent doses of 0.5 mg/kg/min or 1 167
113 168
mortality of patients with shock remains as high as 30% to mg/kg/min have been proposed as thresholds to define
114 169
50%, mainly due to multiorgan failure.4-10 high-dose vasopressor therapy and refractory
115 170
shock.20-23 On the basis of these observations, a
116 The vasopressor dose required to maintain adequate 171
reasonable definition of refractory shock would be an
117 mean arterial pressure (MAP) is one of the strongest 172
118
inadequate response to high-dose vasopressor therapy 173
predictors of short-term mortality in critically ill
119 (defined as $ 0.5 mg/kg/min norepinephrine-equivalent 174
patients.11-14 High doses of catecholamine vasopressors
120 dose).20 Observational studies suggest that, using this 175
can produce a variety of adverse effects, contributing to
121 definition, 6% to 7% of critically ill patients may 176
morbidity and mortality.15,16 The increased mortality in
122 develop refractory shock.21,28 Mortality rates in 177
patients with higher vasopressor requirements reflects
123 patients with refractory shock greatly depend on the 178
124
both a greater severity of underlying illness and 179
definition used (e-Tables 1 and 2), with hospital
125 potentially harmful effects of vasopressor drugs.12,16,17 180
mortality rates generally exceeding 50%.21-24,28-31 There
126 Adverse events are common during catecholamine 181
is no consistent relationship between norepinephrine-
127 therapy for shock, leading some authors to propose that 182
equivalent dose and short-term mortality in patients
128 high catecholamine doses are directly toxic to various 183
with refractory shock, implying that outcomes are poor
129 tissues and organs. This theory may be supported by 184
once a refractory shock state develops independent of
130 evidence suggesting a possible beneficial effect of 185
vasopressor dose.
131 b-blockade in patients with sepsis.18 In addition, the use 186
132 of higher vasopressor doses to achieve a higher MAP 187
133 188
goal in patients with sepsis was associated with increased Pathophysiology of Refractory Shock
134 189
rates of cardiovascular adverse effects, although not with
135 A central pathophysiologic feature of refractory shock is 190
increased mortality.19
136 the impairment of vascular response to catecholamine 191
137 stimulation (Fig 1).20 Reduced catecholamine 192
138 Refractory Shock Definition responsiveness and uncontrolled pathologic vasodilation 193
139 194
There is no universal consensus definition of refractory (vasoplegia) can occur because of changes in receptor
140 195
shock. Proposed definitions include failure to achieve a signaling, metabolic derangements, and depletion of
141 196
BP goal despite vasopressor therapy, need for rescue endogenous vasoactive hormones. Inappropriate
142 197
vasopressor therapy, or need for high vasopressor vasodilation typically occurs from the effects of
143 198
144 doses.20-23 Conventional methods of comparing total inducible nitric oxide synthase (iNOS), which produces 199
145 vasopressor dose among patients include conversion to excessive amounts of vasodilatory nitric oxide (NO). NO 200
146 norepinephrine equivalents (Table 1) or use of one of increases vascular levels of cyclic adenosine 201
147 several previously published scores.4-6,8,10,12,13,23-27 The monophosphate and cyclic guanosine monophosphate 202
148 recent Angiotensin II for the Treatment of High- to trigger vasodilation.32,33 Activation of adenosine 203
149 Output Shock 3 (ATHOS-3) clinical trial used a triphosphate-sensitive potassium channels in vascular 204
150 205
norepinephrine-equivalent dose > 0.2 mg/kg/min to smooth muscle cells prevents calcium entry required for
151 vasoconstriction, representing a final common pathway 206
define refractory shock and reported worse outcomes
152 207
in patients requiring $ 0.5 mg/kg/min of linking metabolic derangements (tissue hypoxia and
153 208
acidosis) and inflammation (including NO production)
154 209
with vasoplegia.20,32 Absolute or relative deficiencies of
155 TABLE 1 ] Converting Vasopressor Doses to 210
Norepinephrine endogenous vasoactive hormones, such as cortisol,
156 211
Q13 Equivalents4-6,8,10,12,23,24,26,27 vasopressin, and angiotensin II, can develop in shock
157 212
158 Norepinephrine states, further decreasing vasopressor 213
159 Drug Dose Equivalent responsiveness.34-36 Not all vascular beds are dilated in 214
160 Epinephrine 0.1 mg/kg/min 0.1 mg/kg/min shock, and microcirculatory defects that create low- or 215
161 Dopamine 15 mg/kg/min 0.1 mg/kg/min no-flow zones are surrounded by areas of profound 216
162 Norepinephrine 0.1 mg/kg/min 0.1 mg/kg/min vasodilation and rapid flow, leading to inadequate tissue 217
163 oxygen delivery.37 The combination of pathologic 218
Phenylephrine 1 mg /kg/min 0.1 mg/kg/min
164 vasodilation with vasoconstriction from vasopressor 219
Vasopressin 0.04 U/min 0.1 mg/kg/min
165 220
drugs produces heterogeneous effects on different

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221 276
Hypoxia, acidosis,
222 277
hyperlactatemia
223 278
224 279
225 280
Reactive oxygen
226 Dysregulated nitric ATP-sensitive K+ channel 281
species
oxide metabolism activation
227 overproduction 282
228 283
229 284
230 Altered microcirculatory flow 285
231 Decreased bactericidal activity Membrane hyperpolarization 286
Endothelial dysfunction
232 Coagulation modulation Cellular relaxation 287
Mitochondrial dysfunction
Dysregulated mitochondrial Vasorelaxation
233 288
respiration
234 289
235 290
236 291
237 Impaired responsiveness to 292
238 catecholamines 293
239 294
240 Vascular smooth 295
Hyperglycemia muscle relaxation
241 296
Hypocalcemia
242 297
Corticosteroid deficiency
243 298
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244 Uncontrolled 299

245 production of NO 300
REFRACTORY
246 and PGI2 301
VASODILATORY SHOCK
247 302
248 Figure 1 – Pathophysiologic mechanisms contributing to refractory vasodilatory shock. Yellow represents initial physiologic insults, orange represents Q18 303
249 shared pathophysiologic mechanisms, and red represents the end result. ATP ¼ adenosine 50 -triphosphate; NO ¼ nitric oxide; PGI2 ¼ prostacyclin. Q14 Q15
304
250 305
251 306
vascular beds, leading to maldistribution of blood cardiac output typically indicate vasodilatory shock.
252 307
flow despite acceptable systemic hemodynamic Despite lack of evidence supporting a survival benefit in
253 308
parameters.38,39 critically ill patients, a pulmonary artery catheter can be
254 309
255
considered when the hemodynamic state remains 310
256 uncertain despite other testing.41,42 311
257 Evaluation of Refractory Shock 312
Patients with inadequate cardiac output should be
258 The first step in the evaluation of refractory shock is to 313
assessed for fluid responsiveness, and objective measures
259 exclude factitious BP measurements and identify the 314
of fluid responsiveness should be used to guide
260 primary cause and reversible secondary contributors, 315
261
resuscitation. Measures of fluid responsiveness 316
such as hypovolemia, uncontrolled vasodilation, pump
262 frequently require patients to undergo mechanical 317
failure, or obstructive shock (Fig 2). Bedside diagnostic
263 ventilation at 8 to 10 mL/kg ideal body weight and be in 318
testing for patients with refractory shock may include a
264 sinus rhythm, which might not always be possible. A 319
combination of hemodynamic, laboratory, and imaging
265 controlled fluid challenge can be considered in the 320
parameters. Empiric broad-spectrum antibiotics are often
266 absence of fluid overload, particularly when measures of 321
considered until sepsis can be excluded.40 An objective
267 fluid responsiveness are indeterminate.40,43 After 322
268 assessment of cardiac output is critical to help guide 323
addressing contributing causes and fluid responsiveness,
269 clinical management, including surrogate measures such 324
initiation and optimization of vasopressor therapy
270 as Doppler-derived estimates, minimally invasive pulse- 325
should be considered (Fig 3).12,20
271 contour analysis, and central venous oxygen saturation.41 326
272 Low cardiac output or central or mixed venous oxygen 327
273 saturation requires further testing to differentiate into Vasopressor Therapy in Refractory Shock 328
274 hypovolemic, cardiogenic, or obstructive shock. Elevated When adequate MAP > 65 mm Hg cannot be 329
275 330
central or mixed venous oxygen saturation levels and high established with other measures, vasopressor therapy

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331 386
Refractory shock
332 Persistent hypotension 387
333 despite vasopressors 388
334 389
335 390
336 Assess cardiac outputa 391
337 & fluid-responsivenessb 392
338 393
339 394
340 Low cardiac output Low cardiac output Low cardiac output High cardiac output 395
341 (+) fluid responsiveness (-) fluid responsiveness ± fluid responsiveness ± fluid responsiveness 396
342 397
343 398
344 Hypovolemic shock Obstructive shock Vasodilatory shock 399
345 Cardiogenic shock Cardiac tamponade Sepsis, anaphylaxis, 400
Hemorrhage
Myocardial infarction Tension pneumothorax sedative/vasodilator drugs,
346 Excessive diuresis
Stress cardiomyopathy 401
Gastrointestinal fluid losses Pulmonary embolism protamine reaction, propofol
347 Myocardial depression Abdominal compartment infusion syndrome, 402
Third-space fluid losses
348 Under-resuscitated sepsis
Cor pulmonale Dynamic hyperinflation metabolic acidosis, 403
349 (auto-PEEP) hypocalcemia 404
350 405
351 406
Diagnostic tests Diagnostic tests Diagnostic tests Diagnostic tests
352 407
• Blood hemoglobin • Echocardiogram • Chest radiograph • Blood cultures
353 • Imaging to identify • Pulmonary artery catheter • Pleural ultrasound • Procalcitonin 408
354 suspected bleeding site Consider inotropes • Echocardiogram • Ionized calcium 409
355 • Cardiac filling pressures Consider mechanical • Bladder pressure • Blood gas analysis 410
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Fluid challenge circulatory support • Ventilator waveform Discontinue offending

356 411
Blood transfusion if ± Fluid challenge medications
357 bleeding Correct underlying Consider antibiotics 412
358 cause Increase vasopressors 413
359 414
360 Figure 2 – Suggested diagnostic approach for identifying reversible contributors to refractory shock, based on assessment of cardiac output and fluid 415
responsiveness. aMeasurement of central or mixed venous oxygen saturation can be used as a surrogate for cardiac output in many patients. bMeasures
361 of fluid responsiveness can include respiratory pulse-pressure or stroke volume variation and passive straight-leg raise. PEEP ¼ positive end-expiratory 416
362 pressure. Q16 417
363 418
364 419
should be initiated. Because untreated or persistent benefit.4,10,46,47 The consensus view is that
365 420
366
hypotension is an important driver of organ norepinephrine should be the recommended first-line 421
367 dysfunction, restoring and maintaining an adequate vasopressor for most critically ill patients in whom 422
368 MAP is a central goal of therapy in refractory shock. A vascular tone needs to be increased.1,12,40 The maximum 423
369 MAP goal > 65 mm Hg seems adequate for most effective dose of norepinephrine remains uncertain, but 424
370 patients, although patients with preexisting hypertension vasopressor responsiveness seems to decline at 425
371 may have a lower risk of kidney injury if a higher MAP norepinephrine doses > 0.5 mg/kg/min.12,20,24 All 426
372 goal is used.19,44 Despite multiple, large randomized vasopressor agents display a log-linear dose response 427
373 controlled trials (RCTs), no vasopressor has been curve with decreasing incremental effectiveness at higher 428
374 conclusively shown to be superior as first-line therapy doses and likely a greater potential for toxicity.12 429
375 430
for vasodilatory shock, and no other vasopressor has Increasing the norepinephrine dose to very high levels
376 431
been found to be superior to norepinephrine for (ie, > 4 mg/kg/min) can increase vascular tone and MAP
377 432
prevention of death.4-6,8 Norepinephrine has been in selected patients, although the potential toxicity of
378 433
379
compared with either dopamine or epinephrine in large this approach remains a concern.48 434
380 RCTs, showing similar or improved clinical outcomes 435
381 and fewer arrhythmias.4,6,8,45 Small RCTs have The use of moderate doses of multiple vasopressors with 436
382 compared norepinephrine and phenylephrine but were complementary mechanisms of action may avoid the 437
383 underpowered for mortality.12 Vasopressin has been toxicity associated with high doses of a single agent, and 438
384 studied in large RCTs as either an alternative or adjunct we advocate for earlier use of rational combination 439
385 to norepinephrine, without evidence of a mortality vasopressor therapy for severe shock.35 On the basis of 440

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441 INCREASING become depleted during shock, leading to relative or 496
SHOCK SEVERITY
442 absolute vasopressin deficiency and pathologic 497
443 Early shock 498
• Identify and treat underlying cause vasodilation that can be reversed by vasopressin
444 499
• Fluid resuscitation based on physiologic measures
supplementation at physiologic doses (0.03-0.04 U/min).36

ESCALATING VASOPRESSOR DOSES

• Norepinephrine monotherapy, if needed
445 500
Vasopressin effectively increases vascular tone and
446 Severe shock 501
• Identify and treat contributing pathophysiology does not exacerbate tachycardia or arrhythmias but can
447 Hypovolemia: fluid resuscitation 502
448
Acidosis or AKI: CRRT and/or alkali reduce cardiac output.12,50 Vasopressin may have a role 503
Hypocalcemia: calcium supplementation
449 • Rational combination vasopressor therapy in maintaining vascular tone during acidemic 504
Vasopressin analogue added to norepinephrine
450 Epinephrine, if inadequate cardiac output
conditions that reduce vascular responsiveness to 505
451 Emerging role for angiotensin II
• Adjunctive agents
catecholamines.36 Vasopressin has been shown in 506
452 Low-dose hydrocortisone multiple studies to increase MAP and decrease 507
High-dose ascorbic acid and/or thiamine
453 508
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Refractory shock
catecholamine requirements, but it has not shown
454 • Identify treatable pathology definitive benefits on mortality and adverse 509
• Initiate rescue therapies
455 Methylene blue events.22,29-31,36 The large, multicenter Vasopressin and 510
456 Hydroxocobalamin 511
Septic Shock Trial (VASST) examined the use of low-
457 Figure 3 – Suggested treatment algorithm for management of vaso- 512
dose (0.03 U/min) vasopressin or norepinephrine
458 dilatory shock.20,24 AKI ¼ acute kidney injury; CRRT ¼ continuous 513
renal replacement therapy. added to baseline catecholamine therapy in patients
459 514
with septic shock and found no difference in
460 515
461
supporting meta-analyses of RCTs, the Surviving Sepsis mortality.5 Decreased mortality was observed with 516
462 Campaign guidelines recommend the addition of vasopressin in patients with less severe shock (baseline 517
463 vasopressin (moderate-quality evidence) or epinephrine norepinephrine requirements < 15 mg/min), but 518
464 (low-quality evidence) for patients with inadequate patients with higher norepinephrine requirements and 519
465 response to catecholamine therapy; no studies directly those requiring multiple vasopressors reported no 520
466 compare these drugs as second-line vasopressors.40 mortality benefit from the addition of vasopressin.5,51 521
467 Epinephrine produces substantial b-adrenergic Patients receiving both vasopressin and corticosteroid 522
468 stimulation that can obviate the need for additional therapy seemed to have the lowest mortality rates in 523
469 inotropic drugs when cardiac output is inadequate.6 524
VASST, suggesting the possibility of synergy between
470 525
Dopamine and phenylephrine are weak vasopressors these agents.51 Recent meta-analyses have yielded
471 526
and are typically not effective in severe or refractory conflicting results regarding whether vasopressin or
472 527
shock; dopamine is associated with an increased rate of other noncatecholamine vasopressors may reduce
473 528
474
cardiac arrhythmias and may worsen outcomes in mortality in vasodilatory shock.46,47,49 The totality of 529
475 cardiogenic shock.12,40,45 the evidence suggests that vasopressin is a safe and 530
476 effective adjunctive vasopressor in patients with shock 531
Clinical end points for hemodynamic support may
477 who are receiving catecholamines. The recent Effect of 532
include adequate urine output, lactate clearance, or
478 Early Vasopressin vs Norepinephrine on Kidney 533
central/mixed venous oxygen saturation.40 There is no
479 Failure in Patients With Septic Shock (VANISH) study, 534
480
added advantage to targeting a supranormal cardiac 535
which compared norepinephrine with vasopressin
481 output in patients with vasodilation. Excessive 536
(titrated up to 0.06 U/min) in early septic shock, did
482 b-adrenergic stimulation by high-dose catecholamines 537
not report any significant differences in mortality or
483 may produce myocardial toxicity and other adverse 538
adverse events, implying that higher vasopressin doses
484 effects, although data supporting the superiority of 539
can be used safely in selected patients.10 Studies
485 catecholamine-sparing vasopressors are limited.15,49 540
comparing low-dose (0.03 U/min or 2.0 U/h) with
486 Epinephrine is known to exacerbate hyperglycemia and 541
487
high-dose (0.06 U/min or 4.0 U/h) vasopressin for 542
lactic acidosis, and predisposes to arrhythmias.6,8 Early
488 refractory shock reported greater hemodynamic effects 543
initiation of combination vasopressor therapy before the
489 with the higher dose.29-31 Use of vasopressin doses 544
onset of refractory shock is expected to yield better
490 > 0.04 U/min can result in an increase in levels of 545
outcomes,5 as was shown with vasopressin (Fig 3).
491 hepatic transaminases and bilirubin.22 However, these 546
492 Vasopressin has been studied as a therapeutic agent for studies were underpowered to show significant 547
493 the management of refractory vasodilatory shock.36 differences in mortality or adverse effects and should 548
494 Hypothalamic-pituitary stores of vasopressin can therefore be interpreted with caution. 549
495 550

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551 Rescue Therapies for Refractory Shock supplementation in critically ill patients have shown that 606
552 low doses of hydrocortisone (200-300 mg/d) can reduce 607
Table 2 summarizes the various rescue treatment
553 608
options for refractory shock. Despite favorable vasopressor requirements and duration of vasopressor
554 609
hemodynamic effects, none of these therapies has been support, independent of standard measures of adrenal
555 610
conclusively shown to reduce mortality of patients after gland function.7,9,34 Despite clear evidence supporting
556 611
the onset of refractory shock, nor has any agent proven the ability of glucocorticoid therapy to increase MAP,
557 612
558 superior in a large RCT. Outcomes of patients with the effects of low-dose hydrocortisone supplementation 613
559 established refractory shock are poor despite the use of on mortality remain uncertain. Low-dose 614
560 these rescue therapies, arguing in favor of earlier hydrocortisone may reduce mortality of patients with 615
561 initiation of better-studied and safe therapies, such as sepsis and vasopressor-dependent shock and multiorgan 616
562 combination vasopressor therapy and glucocorticoid failure.7 Less severely ill patients do not seem to have a 617
563 supplementation. mortality benefit from glucocorticoid therapy; therefore, 618
564 glucocorticoid therapy may not have a role for patients 619
565 Glucocorticoid Therapy with adequate MAP after fluid resuscitation and 620
566 621
Glucocorticoid therapy for the treatment of shock moderate doses of vasopressors.9 The optimal timing of
567 622
remains controversial, with conflicting evidence hydrocortisone initiation remains uncertain, but
568 623
regarding a mortality benefit but clear evidence hydrocortisone therapy should be considered for
569 624
supporting improved shock reversal. Glucocorticoid patients requiring multiple vasopressors (Fig 3).40
570 625
571 receptors augment vascular a-adrenergic responsiveness A synergistic benefit has been reported from the 626
572 and reduce inflammation-mediated vasodilation. combination of hydrocortisone and vasopressin.51,52 The 627
573 Patients with shock may develop relative or functional recommended dosage of hydrocortisone for refractory 628
574 adrenal insufficiency, which could contribute to shock is 100 mg every 8 h or 50 mg every 6 h, without 629
575 refractory vasodilation.34 Clinical trials of corticosteroid the need for fludrocortisone.34,40 630
576 631
577 632
578 633
TABLE 2 ] Potential Rescue Therapies for Refractory Shock
579 634
580 Therapy Dose Mechanism of Action Adverse Effects 635
581 Hydrocortisone Bolus: 50 mg every 6 h or Increased vascular Secondary infection 636
582 100 mg every 8 h catecholamine response Hyperglycemia 637
583 Infusion: 10 mg/h Hypernatremia 638
584 Calcium chloride Bolus: 1-2 g Increased vascular calcium Hypercalcemia 639
Infusion: 20-50 mg/kg/h signaling Inhibition of b-
585 640
adrenergic effects
586 641
Sodium bicarbonate 1-2 mEq/kg Reversal of metabolic acidosis Hypernatremia
587 642
Ionized hypocalcemia
588 Respiratory acidosis 643
589 644
THAM 9 mL/kg (2.7 mEq/kg) up to Reversal of metabolic acidosis Hyperkalemia
590 500 mL over 30-60 min Fluid overload 645
591 646
Methylene blue Bolus: 1-2 mg/kg every 4-6 h Inhibition of NOS Serotonin syndrome
592 Infusion: 0.25-1 mg/kg/h Hypoxia 647
593 Pulmonary 648
594 hypertension 649
595 Hydroxocobalamin 5g Scavenging of NO Interference with 650
596 hemodialysis sensors 651
597 Ascorbic acid 25 mg/kg every 6 h or 1.5 g Increased catecholamine and Minimal 652
598 every 6 h vasopressin synthesis 653
599 Thiamine 200 mg every 12 h Improved lactate clearance Minimal 654
600 Terlipressin (not available in Bolus: 1 mg every 6 h Activation of vasopressin-V1a Reduced cardiac output 655
601 the United States) Infusion: 1.3 mg/kg/h receptors Increased pulmonary 656
602 vascular resistance 657
603 Angiotensin II (not available Starting: 2-10 ng/kg/min Angiotensin II receptor Hypertension 658
604 in the United States) Maximum: 20-40 ng/kg/min activation Metabolic alkalosis 659
605 660
NO ¼ nitric oxide; NOS ¼ nitric oxide synthase; THAM ¼ tris-hydroxymethyl-aminomethane (tromethamine).

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661 Correction of Acidemia calcium essential for cardiovascular function. 716
662 Hypocalcemia is commonly observed in critically ill 717
Although metabolic abnormalities are often associated
663 718
with refractory shock and vasopressor patients, with causes that include chelation of calcium by
664 719
hyporesponsiveness, correction of metabolic citrate in transfused blood products, saponification of
665 720
abnormalities has never been shown to improve clinical the necrotic tissues, acquired parathyroid gland
666 721
outcomes in patients with shock.53,54 Metabolic (lactic) insufficiency, renal 1a-hydroxylase insufficiency,
667 722
668 acidosis is a major contributor to vascular vitamin D deficiency, and acquired calcitriol 723
669 hyporesponsiveness to catecholamine vasopressors.32,55 resistance.61 Severe hypocalcemia can depress 724
670 Tissue hypoperfusion and mitochondrial dysfunction cardiovascular function and produce hypotension.53,62 725
671 from shock contribute to lactic acidosis, and systemic Bolus administration of calcium chloride increases MAP 726
672 acidemia leads to worsening tissue perfusion, triggering by increasing vascular tone without augmenting cardiac 727
673
a vicious cycle of organ dysfunction.55 Vasopressor output but may potentially blunt cardiac b-adrenergic 728
674 responses.63 No evidence suggests that calcium 729
responsiveness declines markedly when arterial pH is <
675 administration improves patient-centered outcomes, 730
7.15 due to impaired catecholamine signaling.54 Sodium
676 731
bicarbonate can be used to reverse acidosis, although and cellular calcium overload is potentially harmful in
677 732
increases in MAP after administration of hypertonic sepsis and shock.53,64,65 Studies have suggested that
678 733
sodium bicarbonate may be due to volume expansion patients taking calcium channel blockers who develop
679 734
and not related to acid-base effects.56 Administration of sepsis may have a lower risk of adverse outcomes,
680 735
681 sodium bicarbonate can produce harmful effects such as arguing against use of high-dose calcium in these 736
682 intracellular acidosis, respiratory acidosis, ionized patients.64,65 737
683 hypocalcemia, hypernatremia, myocardial depression, 738
684 and increased serum lactate levels.54,55 Tris- NO Inhibitors 739
685 hydroxymethyl-aminomethane (tromethamine) is a 740
Unregulated NO overproduction by iNOS is an important
686 741
synthetic nonbicarbonate buffer that can be used as an contributor to vasodilatory shock, and excessive NO
687 742
alternative to sodium bicarbonate, although information may have harmful secondary effects on mitochondrial
688 743
regarding its efficacy and safety is scarce.55 Use of alkali and organ function.32 There has been substantial
689 744
690
therapy requires administration of a substantial volume interest in drugs that inhibit iNOS to improve 745
691 of IV fluid and is at best a temporizing measure. hemodynamic parameters and reverse vasodilatory 746
692
Renal Replacement Therapy
shock. L-NG-monomethyl-arginine (tilarginine) is a 747
693 nonselective nitric oxide synthase (NOS) inhibitor that 748
694 Acute kidney injury associated with severe shock may has been studied in patients with shock.66-68 In patients 749
695 limit clearance of acidemia. Continuous renal with sepsis, NOS inhibitors were shown to increase 750
696 replacement therapy can correct metabolic vascular tone and MAP, leading to vasopressor 751
697 derangements and improve vasopressor responsiveness 752
withdrawal or dose reduction, but were associated with
698 in selected patients with acute kidney injury.57 A shorter increased mortality. The failure of iNOS inhibitors to
753
699 duration between vasopressor initiation and initiation of 754
improve clinical outcomes despite a favorable
700 continuous renal replacement therapy may be associated 755
701
hemodynamic effect casts doubt on the mortality effects 756
with improved outcomes in patients with septic shock of other rescue agents affecting NO signaling for
702 757
who have severe acute kidney injury.58 Observational refractory shock. Increased mortality with NOS inhibitors
703 758
studies of high-volume hemofiltration to clear metabolic may be explained in part by the various beneficial
704 759
705
toxins and inflammatory mediators in patients with physiologic effects of NO signaling that are lost with 760
706 septic shock and acute kidney injury have shown nonselective inhibition of NOS, including maintenance of 761
707 favorable effects on hemodynamic variables but not on microvascular and endothelial function and 762
708 mortality.59,60 Vasopressor requirements are reduced immunomodulatory effects.32 NOS inhibitors represent 763
709 and microcirculatory parameters improved with an important example of a therapy that is associated with 764
710 hemofiltration in some patients, an effect more 765
higher mortality despite increasing MAP. Hence, clinical
711 pronounced with higher volume hemofiltration. 766
outcome studies are needed before these drugs should be
712 767
Calcium applied routinely in refractory septic shock.
713 768
714 Contraction of cardiac and vascular smooth muscle is Methylene blue, a water-soluble dye that inhibits NOS 769
715 770
mediated by intracellular calcium signaling, making and soluble guanylate cyclase, has been evaluated for

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771 refractory vasodilatory shock, particularly after cardiac Future Therapies for Refractory Shock 826
772 surgery.33 Methylene blue seems to reverse vasodilation 827
Terlipressin is a long-acting vasopressin analogue with
773 828
caused by excessive NO signaling and may be effective partial selectivity for the vasopressin-V1a receptor.
774 829
for increasing vascular tone in septic shock or for Terlipressin can increase MAP and reduce vasopressor
775 830
preventing vasoplegia after cardiac surgery.69,70 requirements in vasodilatory shock; however, it is not
776 831
777
Methylene blue may inhibit monoamine oxidase, currently available in the United States.77-79 Terlipressin, 832
778
potentially causing serotonin syndrome via drug-drug administered as a bolus, seems to produce a marked 833
779 interactions,71 and its effect is short, requiring repeated reduction in cardiac output that requires substantial 834
780 dosing or continuous infusion.33,70 However, methylene doses of inotropic support to counteract.77 Continuous 835
781 blue can increase pulmonary vascular resistance and infusion of terlipressin seems to have similar 836
782 worsen oxygenation in some patients.33 effectiveness without the same pronounced reduction in 837
783 cardiac output.78 838
784
Q8 Hydroxocobalamin (Cyanokit; Meridian Medical 839
785 Technologies), a vitamin B12 precursor used clinically to Selepressin is a synthetic selective vasopressin-V1a 840
786 reverse cyanide toxicity, acts as an NO scavenger that receptor agonist that may be effective in refractory 841
787 can reverse NO-mediated vasodilation. Clinical shock.80 As with vasopressin, selepressin restores and 842
788 experience with this agent for off-label use in refractory maintains vascular tone, but it is not associated with the 843
789 shock is limited, but it has been shown to effectively nonvascular adverse effects of vasopressin, such as fluid 844
790 reverse refractory vasodilation in selected patients.72 overload from water retention and thrombosis from von 845
791 Hydroxocobalamin remains in the bloodstream and 846
Willebrand factor release. In a randomized, phase 2 pilot
792 847
urine for days or weeks following administration and study of 53 patients with septic shock, selepressin 2.5 ng/
793 848
can interfere with proper functioning of heme sensors kg/min increased MAP and lowered norepinephrine
794 849
on hemodialysis machines; it should therefore be used requirements more effectively than placebo or a lower
795 850
with caution in patients with acute kidney injury.73 dose of selepressin and may have had a favorable effect
796 851
797 on clinical outcomes. Despite these promising early data, Q9 852
798 Vitamin Deficiency and Repletion a randomized phase 3 trial of selepressin for septic 853
799 shock, the Selepressin Evaluation Programme for Sepsis- 854
Endogenous norepinephrine and vasopressin synthesis
800 Induced Shock–Adaptive Clinical Trial (SEPSIS-ACT),81 855
are governed by enzymes requiring ascorbic acid
801 was terminated due to futility. 856
802
(vitamin C) as a necessary cofactor.74,75 Absolute or 857
803 relative vitamin C deficiency in critically ill patients may Angiotensin II has been recognized for many years as a 858
804 contribute to shock by reducing the availability of these potential therapy for refractory shock.82 Endogenous 859
805 endogenous vasopressors. Administration of high-dose, angiotensin II works with catecholamines and 860
806 IV ascorbic acid (25 mg/kg or 1.5 g every 6 h) may vasopressin to maintain blood pressure, especially in the 861
807 improve inflammation, hemodynamic variables, and face of a hypotensive insult. Patients with sepsis may 862
808 organ function in critically ill patients, even without develop a functional angiotensin-converting enzyme or 863
809 documented vitamin C deficiency. Thiamine (vitamin B1) angiotensin II deficiency, leading to refractory shock. IV 864
810 is an essential cofactor in oxidative energy metabolism, 865
synthetic human angiotensin II has been evaluated in
811 866
specifically lactate metabolism, and thiamine deficiency patients with refractory shock. The Angiotensin II in
812 867
can cause cardiovascular compromise and exacerbate High-Output Shock (ATHOS) pilot study showed
813 868
lactic acidosis.76 In a pilot study of patients with septic favorable hemodynamic effects of angiotensin II
814 869
815
shock, administration of IV thiamine, 200 mg twice daily, infusion in patients with vasodilatory shock who 870
816 failed to improve lactic acid clearance or shock reversal; required high doses of norepinephrine and vasopressin; 871
817 however, in the predefined subgroup of patients with angiotensin II infusion allowed other vasopressors to be 872
818 thiamine deficiency, there was a suggestion of improved discontinued in many patients.35 The recently published Q10 873
819 lactate clearance and lower mortality with thiamine phase 3 ATHOS-3 trial compared angiotensin II 874
820 supplementation. In an observational study of patients infusion (La Jolla Pharmaceutical Company) with 875
821 with septic shock, a protocol combining hydrocortisone, placebo in 321 patients with refractory vasodilatory 876
822 high-dose vitamin C, and thiamine was associated with shock predominantly caused by sepsis, with a median 877
823 878
improved shock reversal and decreased severity of organ norepinephrine-equivalent dose of 0.34 mg/kg/min.
824 879
failure.75 Angiotensin II infusion significantly increased MAP in
825 880

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881 70% of patients by 3 h, although patients with a baseline Other contributions: Editing, proofreading, and reference verification 936
were provided by Scientific Publications, Mayo Clinic.
882 norepinephrine-equivalent dose $ 0.5 mg/kg/min were 937
883 Additional information: The e-Tables can be found in the 938
less likely to respond to angiotensin II. Adverse events Supplemental Materials section of the online article.
884 939
and short-term mortality were not significantly different
885 940
for patients receiving angiotensin II. As with vasopressin References
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926 Dunser MW. Adverse cardiac events during catecholamine 981
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Acknowledgments 18. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control 986
Financial/nonfinancial disclosures: The authors have reported to with esmolol on hemodynamic and clinical outcomes in patients
932 with septic shock: a randomized clinical trial. JAMA. 2013;310(16): 987
CHEST the following: L. W. B. and A. K. K. report a consulting
933 relationship with La Jolla Pharmaceutical Company. L. S. C. is 1683-1691. 988
934 employed by La Jolla Pharmaceutical Company. La Jolla 19. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure 989
Pharmaceutical Company manufactures synthetic human angiotensin target in patients with septic shock. N Engl J Med. 2014;370(17):
935 990
Q11 II, as discussed in this article. None declared (J. C. J., S. V., K. B. K.). 1583-1593.

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23 January 2018
11:48 pm
EO: CHEST-17-2200