A post hoc reanalysis was performed on a 2009 JAMA paper comparing patients randomised to receive or not receive prehospital drugs and iv access for cardiac arrest.
This was done to evaulate the effect of adrenaline/epinephrine. The reason for the reanalysis was that in the original intention-to-treat analysis, some of the following issues may have influenced the results:
Some patients randomised to adrenaline never received it as they had ROSC before the drug could be given, thus yielding a selection bias with the most easily resuscitated patients in the post hoc no-adrenaline group
At least 1 of 5 patients randomised to receive IV access and drugs did not receive adrenaline as it was regarded futile or it was impossible to gain intravenous access
1 of 10 patients randomised to not receive drugs received adrenaline after they had regained spontaneous circulation for > 5 min.
The purpose of this post hoc analysis on the RCT data was to compare outcomes for patients actually receiving adrenaline to those not receiving adrenaline.
The actual use of adrenaline was associated with increased short-term survival, but with 48% less survival to hospital discharge. The improved survival to hospital admission is consistent with the results of a recent Australia study, and the negative association with longer term survival is similar to a multivariate analysis of observational Swedish registry data where patients receiving adrenaline were 57% less likely to be alive after one month.
Yet more evidence that we haven’t found any drugs proven to improve survival in cardiac arrest. At least not until the human studies on sodium nitroprusside come out?
I bet some of you are still going to be giving the epi exactly every four minutes though.
**Update: see Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest – more prospective data from Japan, this time showing epinephrine improves prehospital ROSC, but decreases chance of survival and good functional outcomes 1 month after the event.**
PURPOSE OF THE STUDY: IV line insertion and drugs did not affect long-term survival in an out-of-hospital cardiac arrest (OHCA) randomized clinical trial (RCT). In a previous large registry study adrenaline was negatively associated with survival from OHCA. The present post hoc analysis on the RCT data compares outcomes for patients actually receiving adrenaline to those not receiving adrenaline.
MATERIALS AND METHODS: : Patients from a RCT performed May 2003 to April 2008 were included. Three patients from the original intention-to-treat analysis were excluded due to insufficient documentation of adrenaline administration. Quality of cardiopulmonary resuscitation (CPR) and clinical outcomes were compared.
RESULTS: Clinical characteristics were similar and CPR quality comparable and within guideline recommendations for 367 patients receiving adrenaline and 481 patients not receiving adrenaline. Odds ratio (OR) for being admitted to hospital, being discharged from hospital and surviving with favourable neurological outcome for the adrenaline vs. no-adrenaline group was 2.5 (CI 1.9, 3.4), 0.5 (CI 0.3, 0.8) and 0.4 (CI 0.2, 0.7), respectively. Ventricular fibrillation, response interval, witnessed arrest, gender, age and endotracheal intubation were confounders in multivariate logistic regression analysis. OR for survival for adrenaline vs. no-adrenaline adjusted for confounders was 0.52 (95% CI: 0.29, 0.92).
CONCLUSION: Receiving adrenaline was associated with improved short-term survival, but decreased survival to hospital discharge and survival with favourable neurological outcome after OHCA. This post hoc survival analysis is in contrast to the previous intention-to-treat analysis of the same data, but agrees with previous non-randomized registry data. This shows limitations of non-randomized or non-intention-to-treat analyses.
Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial Resuscitation. 2012 Mar;83(3):327-32
I promised to put some summary notes on the site for those who attended my talk on ‘The REAL Shocked Patient’ for the Australian College of Ambulance Professionals on Tuesday 21st February 2012, so here they are:
Shocked patients are important – they comprise most of the ‘talk and die’ caseload that preoccupies pub conversations between emergency physicians
It’s easy to mistake these patients as less sick than, say, hypoxic ones, but oxygen delivery to the tissues doesn’t just depend on oxygen!
Here’s a dead wombat – someone in the audience knew a worrying amount about wombat anuses.
The 4 Hs and 4 Ts aren’t a very cognitively practical mnemonic for the causes of PEA arrest (which is an extreme form of hypotension)
I prefer the ‘3 plus 3’ rule, which breaks down the causes into three – volume, pump, and obstruction. Obstruction is further broken down into three causes, being tension pneumothorax, cardiac tamponade, and pulmonary embolism:
Let’s look at some cases of shock caused by volume deficit, pump falure, or one of the three causes of obstruction to the circulation:
Case 1: The hypotensive motorcyclist
His low back pain suggested pelvic fracture
Think of ‘blood on the floor and four more’ (chest, abdomen, pelvis/retroperitoneum, long bones) and consider non-bleeding causes such as neurogenic (spinal injury), tension pneumothorax, cardiac tamponade, and finally medical causes/iatrogenic (drug) causes.
Don’t underestimate the importance of pelvis and limb splinting as a haemorrhage control technique in blunt trauma
Ultrasound in flight made thoracic or abdominal bleeding very unlikely, and ruled out tamponade and pneumothorax
Although he was hypotensive, no fluids were given, as he was mentating normally and peripherally well perfused, with a radial pulse. If we gave fluid, we would titrate to the presence of a radial pulse (in blunt trauma) but we don’t want to ‘pop the clot’ by elevating the BP, or make him less able to form effective clots by diluting his blood with crystalloid.
Mortality in trauma sharply rises with systolic BP below 105-110, so recalibrate your definition of hypotension in terms of when you might be concerned, and which patients may benefit from triage to a trauma centre.
Case 2: The child crushed by a wall
Caution regarding lower limb infusions in patients with abdominal / pelvic injuries – the fluid may not get to the heart.
Case 3: The boy stabbed in the upper thigh
In penetrating limb trauma, prehospital options include pressure, elevation, tourniquet, and haemostatic dressings. Foley catheters have been used successfully in transition zones such as the neck or groin.
Case 4: Haematemesis
Should we apply the same principles of permissive hypotension to patients with ‘medical’ bleeding?
The Trendelenburg position doesn’t make a lot of sense – no need to head down the patient, although the act of elevating the legs may ‘autoinfuse’ a bolus of blood to the core circulation, and is recommended by some bodies as a first aid manoeuvre for hypotensive patients in the field prior to iv fluids.
Case 5: The overdose patient with a low blood pressure but otherwise fine.
When don’t I Worry about hypotension? When the patient is:
With it
Warm peripherally
Weeing
and (in hospital) Without a raised lactate
Case 6: Two cases of pump failure: STEMI and complete heart block
Adrenaline infusions can be simply made with a 1mg 1:10000 minijet diluted in a litre of saline and dripped through a peripheral line titrated to BP / HR / mentation / pulses.
In complete heart block (or other bradycardias) with hypotension, percussion pacing is an option of you don’t have access to transcutaneous or transvenous pacing. If you get capture, it’s as effective in terms of stroke volume as a pacing wire.
Case 7: Obstructive shock – tamponade cases
…with resolution of hypotension after drainage by emergency physicians who identified the tamponade on ultrasound, even though they didn’t suspect it clinically. It can be a surprise!
Case 8: Obstructive shock – tension pneumothorax
Patients are often agitated and won’t lie flat. They may complain of ‘tight’ breathing. Crackles and/or wheezes may be heard. The classic description of deviated trachea, absent breath sounds, and hyperresonance are the exception, not the rule. Be suspicious and always palpate for subcutaneous emphysema.
Don’t assume a needle decompression will work – there is debate about the best site but in some adults a standard needle won’t reach the pleural space. If you need to place more than one needle, go for it. As physicians, we do thoracostomies to ensure we’ve hit the spot.
Case 9: Obstructive shock – pulmonary embolism
A tough one prehospital, as the hypotensive ones need fibrinolysis. Fluid may help the hypotension but too much can overdistend the right ventricle which can then impair left ventricular filling, and worsen the patient’s circulatory state. Once again, ultrasound may be invaluable in highlighting PE as a possible cause for shock.
Case 10: Penetrating trauma to the ‘box’ – chest and upper abdomen.
If these patients arrest due to tamponade, early (< 10 minutes) clamshell thoracotomy can be life saving, which means it may need to be done pre-hospital by a HEMS physician to provide a chance of survival. Be on the look out for these and if in doubt activate a medical team (in New South Wales). Like with tension pneumothorax, these patients may be extremely agitated as a manifestation of their shock.
Case 11:Confused elderly male with pyrexia and smelly urine who appears ostensibly ‘normotensive’
…but how many 82 year olds do you know with a BP of 110/57? His acute confusion may be a manifestation of shock and he needs aggressive evaluation in hospital including a lactate measurement. Don’t be afraid to give this guy fluids in the field – you can make a big difference here.
Here are five of the myths I promised to expose:
So…shocked patients can talk and die. Don’t let that happen. Shocked patients can be normotensive, and hypotensive patients might not be shocked. Have a plan for how you might evaluate the 3+3 causes in your setting and what you can use from your medication and equipment list to manage volume, pump, and obstruction issues. You will save many lives if you become a serious shock detective.
The current Surviving Sepsis campaign guidelines recommend that vasopressin should not be administered as the initial vasopressor in septic shock, and that vasopressin at constant dosage of 0.03 units/min may be added to norepinephrine with anticipation of an effect equivalent to that of norepinephrine alone. European intensivists conducted a systematic review to determine vasopressin’s risks and benefits in vasodilatory shock. There was no demonstrated survival benefit but its use is associated with a significant reduction in norepinephrine requirement.
Interestingly, the authors point out: ‘Low-dose vasopressin may help to restore blood pressure in patients with hypotension refractory to catecholamines, and may favor pulmonary vasodilation and increase glomerular filtration rate and plasma cortisol levels’.
My take home: consider its use if an apparent vasodilatory shock state is refractory to catecholamines, but don’t stress if you don’t have access to it (or it will complicate practical aspects of organising resuscitation and transfer), since there’s still no clear evidence for outcome benefit.
OBJECTIVE:
To examine the benefits and risks of vasopressin or its analog terlipressin for patients with vasodilatory shock.
DATA SOURCE:
We searched the CENTRAL, MEDLINE, EMBASE, and LILACS databases (up to March 2011) as well as reference lists of articles and proceedings of major meetings; we also contacted trial authors. We considered randomized and quasirandomized trials of vasopressin or terlipressin versus placebo or supportive treatment in adult and pediatric patients with vasodilatory shock. The primary outcome for this review was short-term all-cause mortality.
STUDY SELECTION:
We identified 10 randomized trials (1,134 patients). Six studies were considered for the main analysis on mortality in adults.
DATA EXTRACTION AND SYNTHESIS:
The crude short-term mortality was 206 of 512 (40.2%) in vasopressin/terlipressin-treated patients and 198 of 461 (42.9%) in controls [six trials, risk ratio (RR) = 0.91; 95% confidence interval (CI) 0.79-1.05; P = 0.21; I (2) = 0%]. There were 49 of 463 (10.6%) patients with serious adverse events in the vasopressin/terlipressin arm and 51 of 431 (11.8%) in the control arm (four trials, RR = 0.90; 95% CI 0.49-1.67; P = 0.75; I (2) = 26%). Metaregression analysis showed negative correlation between vasopressin dose and norepinephrine dose (P = 0.03).
CONCLUSIONS:
Overall, use of vasopressin or terlipressin did not produce any survival benefit in the short term in patients with vasodilatory shock. Physicians may value the sparing effects of vasopressin/terlipressin on norepinephrine requirement given its apparent safe profile.
An editorial1 reviewing options for circulatory support in patients with cardiogenic shock argues that traditional inotrope therapy may be replaced by newer alternatives that have a less detrimental effect on myocardial oxygen demand.
Newer inotropic agents include levosimendan, istaroxime, and omecamtiv mecarbil. Mechanical therapies include intra-aortic balloon pumps (IABP), ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO).
Levosimendan is an inodilator, with the following characteristics:
stabilises the myocardial calcium-troponin C complex
activates adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle and cardiac mitochondria,
acts as a traditional phosphodiesterase inhibitor at higher doses
improved cardiac output and a reduction in filling pressures compared with dobutamine
may also improve diastolic function by increasing relaxation rate
modulates the neuroendocrine response to heart failure by reducing brain natriuretic peptide levels
has anti-apoptotic and anti-inflammatory effects
renal function may also improve
is associated with a similar risk of ventricular arrhythmias to dobutamine
increases risk of new onset atrial fibrillation
has conflicting literature surrounding mortality
has shown a lack of consistent outcome benefits in studies
may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively2.
Istaroxime, a novel inotrope with positive lusitropic (cardiac relaxant) effects3:
is an inhibitor of the sodium-potassium-ATPase (resulting, like digoxin, in elevated intracellular calcium) with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA)
provides a dose-dependant increase in cardiac output without significant change in heart rate or arrhythmia
in one study reducesd pulmonary capillary wedge pressure, increased systolic blood pressure, and reduced heart rate and left ventricular end-diastolic volume
requires further clinical evaluation.
Omecamtiv mecarbil is a cardiac myosin activator. This new drug:
improves myocardial contraction by increasing the hydrolysis of ATP by myosin ATPase
this produces the power stroke between actin and myosin and subsequent shortening of sarcomere length
in phase-2a studies in patients with systolic heart failure it demonstrated improved stroke volume without an increase in heart rate, although cardiac ischaemia emerged at high plasma concentrations4,5.
PURPOSE OF REVIEW: ICU patients frequently develop low output syndromes due to cardiac dysfunction, myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be useful in restoring hemodynamic parameters and improving peripheral organ perfusion, but can increase short-term and long-term mortality in these patients. Novel inotropes may be promising in the management of ICU patients, having no serious adverse effects. This review summarizes all the current knowledge about the use of conventional and new inotropic agents in various clinical entities of critically ill patients.
RECENT FINDINGS: In recent European Society of Cardiology guidelines, inotropic agents are administered in patients with low output syndrome due to impaired cardiac contractility, and signs and symptoms of congestion. The most recommended inotropes in this condition are levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B). Recent data indicate that levosimendan may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan can be effectively used for weaning of mechanical ventilation in postcardiac surgery patients and has also cardioprotective effect as expressed by the absence of troponin release in this patient population. Finally, new agents, such as istaroxime and cardiac myosin activators may be safe and improve central hemodynamics in experimental models of heart failure and heart failure patients in phase II clinical trials; however, large-scale randomized clinical trials are required.
SUMMARY: In an acute cardiac care setting, short-term use of inotropic agents is crucial for the restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning of cardiosurgery. New promising agents should be tested in randomized clinical trials.
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3. Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output. Discov Med. 2011 Aug;12(63):141-51 Free Full Text
[EXPAND Abstract]
Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that impaired Ca2+ cycling may contribute to myocardial dysfunction. Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na-K ATPase inhibition may increase contractility (inotropy) and facilitate active relaxation (lusitropy), improving both systolic and diastolic functions. Istaroxime, a novel luso-inotrope that activates SERCA2a and inhibits the Na-K ATPase, is currently in phase II clinical development and has been shown to improve systolic and diastolic functions and central hemodynamics, increase systolic but not diastolic blood pressure, and decrease substantially heart rate. Irrespective of its clinical utility, the development of istaroxime has evolved our understanding of the clinical importance of inhibiting the Na-K ATPase in order to obtain a clinically significant effect from SERCA2a activation in the setting of myocardial failure.
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4. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study Lancet. 2011 Aug 20;378(9792):667-75
[EXPAND Abstract]
BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.
METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.
FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.
INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.
FUNDING: Cytokinetics Inc.
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5. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial Lancet. 2011 Aug 20;378(9792):676-83
[EXPAND Abstract]
BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure.
METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442.
FINDINGS: T45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged.
INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent.
It’s become popular to use the term ‘vasopressors’ or just ‘pressors’ when noradrenaline/norepinephrine or even (in some places still) dopamine are given. I have resisted this trend and continue to use the term ‘vasoactive’ drugs, on the basis that the effects they produce (and that we may desire) are not limited to a pure alpha adrenergic effect on vascular tone, but they have effects on heart rate and contractility too (as well as preload through venous effects). If you don’t believe me about noradrenaline/norepinephrine, then check out one of my favourite critical care papers of all time: the CAT study.
There are of course real pressors out there – phenylephrine acts on alpha receptors, as does methoxamine. Metaraminol predominantly acts on alpha receptors but does also cause some release of noradrenaline/norepinephrine.
Why is this important? All these drugs will fix hypotension, right? Yes, they should. However should blood pressure be our main treatment goal? What we’re really interested in is organ perfusion, which depends on regional blood flow to vital organs. It’s possible that a drug could fix the measured blood pressure and give a nice ‘macroscopic’ number, while at the same time reducing cardiac output and adversely affecting regional blood flow to organs through local vasoconstrictive effects. My view is that this is more likely with pure ‘pressors’ (like phenylephrine), which is why I avoid them in septic shock and opt for catecholamine infusions (noradrenaline/norepinephrine).
This is important in my practice setting of retrieval medicine, where, prior to interfacility transport, physicians might sometimes be tempted to ‘push pressors’ peripherally rather than insert a central venous catheter and commence a catecholamine infusion. While the former approach might be more expeditious and make the vital signs chart look pretty, one wonders about what effect this is having on tissue oxygen delivery.
A fascinating review of papers on pressor physiology1 suggests these agents have the following effects:
conflicting data on changes in myocardial perfusion
increase both left and right heart afterload
decrease venous compliance with the potential to increase venous return although the impact of this on cardiac output is controversial
controversial effect on cerebral bloodflow
decrease bloodflow to the kidneys
adverse affects on gastrointestinal tract bloodflow
abstract1
Phenylephrine and methoxamine are direct-acting, predominantly α(1) adrenergic receptor (AR) agonists. To better understand their physiologic effects, we screened 463 articles on the basis of PubMed searches of “methoxamine” and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Both methoxamine and phenylephrine increase cardiac afterload via several mechanisms, including increased vascular resistance, decreased vascular compliance, and disadvantageous alterations in the pressure waveforms produced by the pulsatile heart. Although pure α(1) agonists increase arterial blood pressure, neither animal nor human studies have ever shown pure α(1)-agonism to produce a favorable change in myocardial energetics because of the resultant increase in myocardial workload. Furthermore, the cost of increased blood pressure after pure α(1)-agonism is almost invariably decreased cardiac output, likely due to increases in venous resistance. The venous system contains α(1) ARs, and though stimulation of α(1) ARs decreases capacitance and may transiently increase venous return, this gain may be offset by changes in afterload, venous compliance, and venous resistance. Data on the effects of α(1) stimulation in the central nervous system show conflicting changes, while experimental animal data suggest that renal blood flow is reduced by α(1)-agonists, and both animal and human data suggest that gastrointestinal perfusion may be reduced by α(1) tone.
A review of clinical articles2 reveals few evidence-based indications for true pressors. Possible situations where they may be of benefit include intraoperative hypotension, aortic stenosis, during cyanotic episodes in Tetralogy of Fallot, and some obstetric situations. In the setting of sepis, phenylephrine has been compared with noradrenaline in which an initial pilot study found a statistically significant reduction in creatinine clearance and increase in arterial lactate after initiating the phenylephrine infusion. However a subsequent randomised controlled comparison of phenylephrine with noradrenaline/norepinephrine did not show differences in cardiopulmonary performance, global oxygen transport, or regional hemodynamics, although there were only 16 patients in each group3.
abstract2
Phenylephrine is a direct-acting, predominantly α(1) adrenergic receptor agonist used by anesthesiologists and intensivists to treat hypotension. A variety of physiologic studies suggest that α-agonists increase cardiac afterload, reduce venous compliance, and reduce renal bloodflow. The effects on gastrointestinal and cerebral perfusion are controversial. To better understand the effects of phenylephrine in a variety of clinical settings, we screened 463 articles on the basis of PubMed searches of “methoxamine,” a long-acting α agonist, and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Phenylephrine has been studied as an antihypotensive drug in patients with severe aortic stenosis, as a treatment for decompensated tetralogy of Fallot and hypoxemia during 1-lung ventilation, as well as for the treatment of septic shock, traumatic brain injury, vasospasm status-postsubarachnoid hemorrhage, and hypotension during cesarean delivery. In specific instances (critical aortic stenosis, tetralogy of Fallot, hypotension during cesarean delivery) in which the regional effects of phenylephrine (e.g., decreased heart rate, favorable alterations in Q(p):Q(s) ratio, improved fetal oxygen supply:demand ratio) outweigh its global effects (e.g., decreased cardiac output), phenylephrine may be a rational pharmacologic choice. In pathophysiologic states in which no regional advantages are gained by using an α(1) agonist, alternative vasopressors should be sought.
These review articles reinforce my own bias against the use of pure pressors in septic shock, although clearly more clinical research is needed. I am inclined to agree with the reviewers’ concluding statement: …in all clinical settings, phenylephrine reduces cardiac output, and in most clinical settings has been shown to significantly increase LV afterload. Thus, only in instances in which its regional effects are thought to outweigh its global effects should phenylephrine be used for the treatment of hypotension.
1. The physiologic implications of isolated alpha(1) adrenergic stimulation Anesth Analg. 2011 Aug;113(2):284-96
2. The clinical implications of isolated alpha(1) adrenergic stimulation Anesth Analg. 2011 Aug;113(2):297-304
3. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial Crit Care. 2008;12(6):R143 Full Text available here
A double blind randomised controlled trial showed significantly better rates of return of spontaneous circulation and hospital admission with the use of adrenaline (epinephrine) compared with placebo. This effect was observed with both shockable and non-shockable initial cardiac arrest rhythms. There was no statistically significant difference in the primary outcome of survival to hospital discharge.
Interesting but unfortunate political factors appear to have prevented recruitment to the required numbers of patients for this study so it is underpowered for its primary outcome of survival to hospital discharge, which in the adrenaline group was double that in the placebo group, although this did not reach statistical significance. What was supposed to be a multi-centre study became a single centre one and it was not possible to continue as the study drugs reached their expiry date and no additional funding was available.
So do ROSC and survival to admission matter? The authors make the following point:
While not the primary outcome of our study, ROSC is an increasingly important clinical endpoint as the influence of post resuscitation care interventions (i.e.: therapeutic hypothermia, managing underlying cause, organ perfusion and oxygenation) on survival to hospital discharge are recognised.
Optimum dose and timing of adrenaline remain unknown, along with whether it impacts on long-term outcomes.
BACKGROUND: There is little evidence from clinical trials that the use of adrenaline (epinephrine) in treating cardiac arrest improves survival, despite adrenaline being considered standard of care for many decades. The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest.
METHODS: We conducted a double blind randomised placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest. Identical study vials containing either adrenaline 1:1000 or placebo (sodium chloride 0.9%) were prepared. Patients were randomly allocated to receive 1ml aliquots of the trial drug according to current advanced life support guidelines. Outcomes assessed included survival to hospital discharge (primary outcome), pre-hospital return of spontaneous circulation (ROSC) and neurological outcome (Cerebral Performance Category Score – CPC).
RESULTS: A total of 4103 cardiac arrests were screened during the study period of which 601 underwent randomisation. Documentation was available for a total of 534 patients: 262 in the placebo group and 272 in the adrenaline group. Groups were well matched for baseline characteristics including age, gender and receiving bystander CPR. ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR=3.4; 95% CI 2.0-5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR=2.2; 95% CI 0.7-6.3). All but two patients (both in the adrenaline group) had a CPC score of 1-2.
CONCLUSION: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.
Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial Resuscitation. 2011 Sep;82(9):1138-43
A case report describes a patient with right ventricular cardiogenic shock due to a dissected right coronary artery1. There was deterioration despite fluid, inotropic and intraaortic balloon pump therapy, followed by improvement with the introduction of inhaled nitric oxide (iNO) at 12 to 15 ppm (a selective pulmonary vasodilator), to the point where vasoactive medication was withdrawn. The cessation of iNO was associated with deterioration which resolved with its reintroduction. It was more gradually withdrawn and the patient made a good recovery.
The rationale for the use of iNO in patients with acute RV heart failure due to MI is afterload reduction without systemic hypotension.
It has been shown to improve haemodynamics in RV MI patients with cardiogenic shock in a previous case series2 (abstract below) in which its effects on pulmonary vasodilation are thought be beneficial. In RV MI with shock increased pulmonary vascular tone is postulated to result from the following mechanisms:
A low cardiac output results in a decreased mixed venous blood oxygen content, which enhances pulmonary artery vasoconstriction.
The intravenous infusion of alpha-adrenergic vasoconstrictors can contribute to pulmonary vasoconstriction.
Mechanical ventilation with positive end-expiratory pressure can increase the pulmonary vascular resistance through compression of the pulmonary vasculature.
Interstitial pulmonary edema, which may occur in some patients with coexisting LV dysfunction, can also cause pulmonary constriction
OBJECTIVES: We sought to determine whether or not inhaled nitric oxide (NO) could improve hemodynamic function in patients with right ventricular myocardial infarction (RVMI) and cardiogenic shock (CS).
BACKGROUND: Inhaled NO is a selective pulmonary vasodilator that can decrease right ventricular afterload.
METHODS: Thirteen patients (7 males and 6 females, age 65 +/- 3 years) presenting with electrocardiographic, echocardiographic, and hemodynamic evidence of acute inferior myocardial infarction associated with RVMI and CS were studied. After administration of supplemental oxygen (inspired oxygen fraction [F(i)O(2)] = 1.0), hemodynamic measurements were recorded before, during inhalation of NO (80 ppm at F(i)O(2) = 0.90) for 10 min, and 10 min after NO inhalation was discontinued (F(i)O(2) = 1.0).
RESULTS: Breathing NO decreased the mean right atrial pressure by 12 +/- 3%, mean pulmonary arterial pressure by 13 +/- 2%, and pulmonary vascular resistance by 36 +/- 8% (all p < 0.05). Nitric oxide inhalation increased the cardiac index by 24 +/- 11% and the stroke volume index by 23 +/- 12% (p < 0.05). The NO administration did not change systemic arterial or pulmonary capillary wedge pressures. Contrast echocardiography identified three patients with a patent foramen ovale and right-to-left shunt flow while breathing at F(i)O(2) = 1.0. Breathing NO decreased shunt flow by 56 +/- 5% (p < 0.05) and was associated with markedly improved systemic oxygen saturation.
CONCLUSIONS: Nitric oxide inhalation results in acute hemodynamic improvement when administered to patients with RVMI and CS.
A small retrospective study suggests adrenal insufficiency is common in kids with septic shock, and that steroid administration in these children was associated with a decrease in vasoactive drug requirements.
INTRODUCTION: Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion.
HYPOTHESIS: We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need.
METHODS: Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids.
RESULTS: Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039).
CONCLUSIONS: Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.
Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock Crit Care Med. 2011 May;39(5):1145-50
I’m always on the look-out for evidence to guide vasoactive drug therapy, an area where much dogma is spouted by many who have not read the literature. Here’s a small (note: pilot) study comparing two strategies for cardiogenic shock. The higher heart rate and lactate with epinephrine (adrenaline) are consistent with the findings of the great CAT study; this is of interest, but not necessarily clinically significant nor practice changing.
OBJECTIVE: There is no study that has compared, in a randomized manner, which vasopressor is most suitable in optimizing both systemic and regional hemodynamics in cardiogenic shock patients. Hence, the present study was designed to compare epinephrine and norepinephrine-dobutamine in dopamine-resistant cardiogenic shock. DESIGN: Open, randomized interventional human study. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Thirty patients with a cardiac index of <2.2 L/min/m and a mean arterial pressure of <60 mm Hg resistant to combined dopamine-dobutamine treatment and signs of shock. Patients were not included in cases of cardiogenic shock secondary to acute ischemic events such as myocardial infarction. Noninclusion criteria also included immediate indication of mechanical assistance. INTERVENTIONS: Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain a mean arterial pressure of between 65 and 70 mm Hg with a stable or increased cardiac index. MAIN RESULTS: Both regimens increased cardiac index and oxygen-derived parameters in a similar manner. Patients in the norepinephrine-dobutamine group demonstrated heart rates lower (p<.05) than those in the epinephrine group. Epinephrine infusion was associated with new arrhythmias in three patients. When compared to baseline values, after 6 hrs, epinephrine infusion was associated with an increase in lactate level (p<.01), whereas this level decreased in the norepinephrine-dobutamine group. Tonometered PCO2 gap, a surrogate for splanchnic perfusion adequacy, increased in the epinephrine-treated group (p<.01) while decreasing in the norepinephrine group (p<.01). Diuresis increased in both groups but significantly more so in the norepinephrine-dobutamine group, whereas plasma creatinine decreased in both groups. CONCLUSIONS: When considering global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, epinephrine is associated with a transient lactic acidosis, higher heart rate and arrhythmia, and inadequate gastric mucosa perfusion. Thus, the combination norepinephrine-dobutamine appears to be a more reliable and safer strategy.
Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study Crit Care Med. 2011 Mar;39(3):450-5
Noradrenaline (norepinephrine) may improve blood pressure in part through its venoconstriction effects, providing more venous return to the heart which increases cardiac output. A study of septic shock patients supports this.
An accompanying editorial by Drs Milzman and Napoli comments: “This study tells us something we probably already knew, that norepinephrine (NE) has the ability to provide venoconstriction, increase central venous pressure, provide a marginal increase in cardiac output, and improve the MAP in patients with septic shock. Importantly, it also demonstrates that Passive Leg Raise (PLR) continues to be a good predictor of preload responsiveness even in the presence of low doses of NE.”
OBJECTIVE: To assess the effects of norepinephrine on cardiac preload, cardiac index, and preload dependency during septic shock. DESIGN: Prospective interventional study. SETTING: Medical Intensive Care Unit. PATIENTS: We included 25 septic shock patients (62 ± 13 yrs old, Simplified Acute Physiology Score II 53 ± 12, lactate 3.5 ± 2.1 mmol/L, all receiving norepinephrine at baseline at 0.24 [25%-75% interquartile range: 0.12-0.48] μg/kg/min) with a positive passive leg raising test (defined by an increase in cardiac index ≥10%) and a diastolic arterial pressure ≤40 mm Hg. INTERVENTIONS: We performed a passive leg raising test (during 1 min) at baseline. Immediately after, we increased the dose of norepinephrine (to 0.48 [0.36-0.71] μg/kg/min) and, when the hemodynamic status was stabilized, we performed a second passive leg raising test (during 1 min). We finally infused 500 mL saline. MEASUREMENTS AND MAIN RESULTS: Increasing the dose of norepinephrine significantly increased central venous pressure (+23% ± 12%), left ventricular end-diastolic area (+9% ± 6%), E mitral wave (+19% ± 23%), and global end-diastolic volume (+9% ± 6%). Simultaneously, cardiac index significantly increased by 11% ± 7%, suggesting that norepinephrine had recruited some cardiac preload reserve. The second passive leg raising test increased cardiac index to a lesser extent than the baseline test (13% ± 8% vs. + 19% ± 6%, p < .05), suggesting that norepinephrine had decreased the degree of preload dependency. Volume infusion significantly increased cardiac index by 26% ± 15%. However, cardiac index increased by <15% in four patients (fluid unresponsive patients) while the baseline passive leg raising test was positive in these patients. In three of these four patients, the second passive leg raising test was also negative, i.e., the second passive leg raising test (after norepinephrine increase) predicted fluid responsiveness with a sensitivity of 95 [76-99]% and a specificity of 100 [30-100]%. CONCLUSIONS: In septic patients with a positive passive leg raising test at baseline suggesting the presence of preload dependency, norepinephrine increased cardiac preload and cardiac index and reduced the degree of preload dependency.
Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients Crit Care Med 2011;39(4):689-94