Challenging the outcome of advanced cardiac surgery and role of critical care management

Case study & review of literature

Mohsen Salah Abd Elazeem Mahmoud , MD ; PhD Critical Care Medicine

Associate Professor Cairo University Egypt KFMMC Cardiac Critical Care Consultant KSA

AGENDACase presentation

Review of literature Case progression and outcome

Conclusion

Open discussion

Case Presentation 43 years old male patient known to be

hypertensive, dyslipidemic and IHD .S/P PCI for LAD 4 months ago in the referring

hospital. Presented by ACS , coronary angiography

revealed significant instent stenosois in LAD with non significant lesions in LCX and RCA .

Patient was hemodynamicaly unstable preoperative although being on full anti-ischemic measures.

Laboratory profile is unremarkable .Echocardiography showed normal LV function,

LVH , with apical septal hypokinesia and significant diastolic dysfunction.

Preoperative Medication AspirinPlavixStatin ACE inhibitor NitroglycerinCalcium channel blockers Heparin infusion

Significant dynamic ECG changes

Significant dynamic ECG changes & conduction defect

Surgical intervention

On bypass CABG offering 2 grafts .

Perioperative major events : pre induction sever chest pain followed by ST elevation so urgent sternotomy

and CPB 2 graft were implanted LIMA to LAD & SVG to Diagonal .

Post off bypass pt. complicated by sever hypotension and still ST segment elevation occurred on dynamic basis with intermittent conduction defect necessitate cardiac pacing VVI.

Revision of grafts and checking the flow showed NAD.

IABP inserted with escalation of Inotropic support with poor outcome .

Paroxysmal ST elevation consistent with hypotensive episodes and conduction

defects although full HD supports.

Bleeding was significantly of concern which was controlled by blood product and surgical hemostasis

Reccurent attempt of chest closure failed due to extensive tissue edema and tamponading effects so skin closed and sternum kept open .

Follow up ABGs & VBGs showed lactic academia and the highest lactate was 14 and arterial venous saturation difference ranging between 25 to 40

Due to ongoing ischemic events urgent coronary angiography was requested for reassessment of grafts and coronaries .

Post operative coronary angiography revealed

Significant stenosis distal to LIMA implantation to LAD so PCI and stent had being inserted .

Surprisingly still the patient had ST segment elevation and conduction defect and the LIMA showed significant spasm which is partially resolved by Nitroglycerin flush

No more changes in the patient condition with same paroxysms of ischemic ST elevation and hemodynamic instability

All invasive intervention measures had been utilized and still the patient had ST elevation, conduction defect and hemodynamic decompensation& hypoperfusion .

After consumption of all surgical and cardiac invasive intervention

weapons it is NOW

critical care medicine challenge

Patient referred to CSICU with the following status : Epinephrine 0.6 μg /kg /min and norepinephrine 0.5 μg /kg/min IABP full augmentation 1:1Follow up ABGs showed lactate level more than 15 , PO2/FIo2

consistent with moderate ARDS ,mixed respiratory and metabolic acidosis .

Elevated liver enzymes , thrombocytopenia & leukocytosis.Rising creatinine consistent with oliguria. Pulmonary artery catheter inserted for serial HD parameters follow

up : SVR 400 to 500  dynes · sec/cm5

CI 1.9 to 2.6  l/min/m2

PAWP 14  mmHgMAP 40 to 55  mmHgRAP 8 to 12  mmHgHR 40 to 110 / minStill had paroxysmal attacks ST elevation & conduction defects . worsening of HD profile consistent with sedation and muscle

relaxant management .

what priority to tackle Main Pathological challengesVasospasic angina Circulatory failure ….????Diastolic heart failure & conduction defects ARDS. Organs dysfunction. Open chest with high incidence of wound

sepsis

Target Directed Therapy&

Drug pathology interaction Circulatory support & Vasoplegic syndrome

management Pulmonary

Management

Upgrading of cardiac pacing

to DDD bedside

Vassospastic angina mangment (modified triple H therapy ?!)

Wound sepsis prophylaxis & organs support management

Sedation analgesia

management

CARDIOPULMONARY BYPASS &

VASOPLEGIC SYNDROM

Cardio-Pulmonary BypassThe use of the cardiopulmonary bypass (CPB) machine during

cardiac surgery has become a widely employed practice.

Although CPB simplified cardiac surgery , it had also major adverse effects on a patient’s body organs .

These include complications of the immune system, heart, lungs, kidneys, and brain and physical harm.

Pathophysiological effects of CPB

The Negative Effects of the Cardiopulmonary Bypass: SIRS activation

Once the inflammatory response is activated, the body releases many different components. Complement is one of these inflammatory components that consists of several different elements. Two of these, C5a and C3a, show to be significantly elevated after CPB .

Cytokines, such as tumor necrosis factor (TNF) and several of the interleukins (IL), as IL-8 and IL-6 are also a major component of the inflammatory response that may be increased (Laffey et al., 2002).

Other elevated inflammatory components due to CPB include monocytes, neutrophil , and leukocyte activation .

All the above reactions interact to hit the endothelial system , release Oxygen free radicle , activation of platlets andd malignant production of nitic oxide and arachidonic acid metabolism

Pathophysiology of CPBApproximately 20% of low-risk patients develop

complications following CPB (Laffey et al., 2002)

Once the endothelium of the microcirculation is malfunction, its surface becomes more susceptible to activated platelet with subsequent microcirculatory failure with excessive production of NO resulting impairment of tissue perfusion .

The generalized inflammatory process contributes to multi-organ failure or dysfunction (Laffey et al., 2002) when proinflammatory mediators are elevated relatively to antiinflammatory mediators (Cremer et al., 1996).

Pathological effect of CPB

These systemic inflammatory immune response participate in all complications post CPB including Pulmonary dysfunction, (Atelectasis, ALI, ARDS,PHTN,

Effusion ) AKI , Neurological (structural or functional ) &Hemodynamic decomposition by different presentation

VASOPLEGIC SYNDROME Vasoplegic syndrome (VS) is an integration of adverse effect of

general anesthesia and / or cardiopulmonary bypass in potential high risk patients expressed as refractory hemodynamic decompensation to fluid and vasopressor resuscitation manifested by :

Low SVR < 700dynes · sec/cm5 during intravenous norepinephrine infusion more than 0.5 μg/kg/ min

Cardiac index >2.5 L/min/m2 , Mean Arterial blood pressure <50 mmHg,Right atrial pressure <5 mmHg, Left atrial pressure <10 mmHg

VASOPLEGIC SYNDROME

The incidence of VS in cardiac surgical patients is 8% to 10 %, but may increase up to 50% of so sick patients preoprativly & those who were taking renin-angiotensin system (RAS) antagonists.

 In cardiac surgical patients with persistent hypotension in the postoperative period, the associated mortality approaches 25% to 40%

It can be also associated with, severe sepsis, anaphylaxis and hemodialysis

Predisposing Factors of VS Independent risk factors for post-operative VSPre operative Intravenous heparin association up to 55.6%Pre operative renin-angiotensin system (RAS) antagonists up to 44.4 %Pre operative Calcium channel blockers up to 47.2% Other Risk factors (Exhaustion of Catecholamine Drive and Immune dysfunction )Beta-blockers,Protamine use, Myocardial dysfunction, Diabetes mellitus, Heart transplant, Higher added EuroSCORE, Pre-cardiopulmonary bypass (CPB) hemodynamic instability, Valvular and Heart Failure Surgery, Long duration of CPB,Ventricular assist device insertion

Pathogenesis of V.S.

CPB mediated mechanism through:  Cytokine and inflammatory mediators . Endothelial injury.Nitric oxide-mediated smooth muscle

relaxation. Catecholamine receptor down regulation.Cell hyperpolarization.

Pathogenesis

Nitric Oxide synthesis and Guanylate Cyclase activation and its action on vascular smooth muscle play a corner stone in pathogenesis of VS.Nitric oxide is produced by two types of nitric oxide

synthase:A constitutive type &An inducible type. The inducible synthase is produced in vascular smooth-muscle cells, cardiac myocytes by different inflammatory mediators

Nitric Oxide

•nitric oxide synthase:•A constitutive type •&•An inducible type

Gaunylat

Cyclase

cGMP

• Vascular Dilatation

• Myocardial suppression

IL1 & OFR

•CPB mediated inflammatory response

Gaunylat Cyclase

cGMP • Vascular Dilatation• Myocardial suppression

Vasoplegic Syndrome

PathogenesisUnder normal physiologic circumstances, blood pressure is maintained via three integrated systems : The sympathetic system (Major role ). The renin-angiotensin system The Vasopressinergic system (minor role ) .

Sympathetic Nervous System

Renin Angiotensin system

Vasopressinergic system

PathogenesisMost anesthetic drugs reduce the influence of the sympathetic

system on cardiovascular tone with dependence on RAS and vasopressinergic system .

 RAS antagonists such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) block the RAS response to hypotension.

Endogenous release of vasopressin (AVP) occurs to compensate for the blockage of both the RAS and the sympathetic nervous system, but this is not resolve the hypotension due to its low concentration secondary to depletion of neurohypophyseal stores of vasopressin after profound osmotic stimulation and after sustained baroreflex stimulation .

Types of Vasoplegic Syndrome

Catecholamine Sensitive

Catecholamine Resistant

The Rational Of Management Early suspicion and prediction specially in

combined presentation with other illness ….TIME IS LIFE

Early intervention (to diagnose and to treat )…. Pharmacological therapy ……….a lot of debate Aggressive management……….. Perfusion Directed Therapy…….Dedicated meticulous monitoring( HD profile ,

pulmonary function , renal function ,neuropsychiatric status , hematological status , infection and sepsis and others )

Management of associated problems

Critical Care Management Fluid resuscitation for optimizing filling pressures(GDT)VasopressorsNorepinephrine: mostly will be resistant (receptor mediated

resistance ) Vasopressin: caused significant increases in mean arterial

pressure and systemic vascular resistance, and resulted in a marked reduction in norepinephrine doses, without considerable changes in cardiac index. the efficacy of vasopressin in clinical scenarios in which catecholamine are ineffective with consideration of serious side effects of aggravating mesenteric ischemia and reduction of urine output that may limit its usage

????????????????????????????

Methylene Blue Generaly It is approved for oral and intravenous administration in the

setting of methemoglobinemia, and as a surgical tracer dye for detection of fluid leak.

It is available as a solution 10mg/ml, its oral absorption ranges from 53-97%,

It is eliminated in bile, feaces and urine as leucomethyle blue.

It is used in all age groups

The onset of the hemodynamic effects of methylene blue is relatively rapid

Evidence in post-operative useMethylene blue has predominantly been used to reverse

vasoplegia in a post-operative setting. Several groups of studies have shown that the post-operative administration of a single dose of MB in VS can restore SVR.

Kofidis et al had being demonstrated successful use of MB for vasoplegia in a post-transplant patient

Evidence in post-operative useLevin and colleagues randomized 56 patients with vasoplegia to receive IV MB (1.5

mg/kg over 1-h) or placebo. There were no deaths in the MB group and six deaths (21.4%) in the placebo group.

Methylene blue reversed vasoplegia in about 2 h, while in those treated with vasopressors (28.6%) only, vasoplegia persisted for more than 48 h with progression to MOFS .

Intra-operative use of MBGrayling and Deakin added MB to the pump prime as treatment

for septic endocarditis during a valve operation, and followed this up with a post-operative infusion.

Evora and colleagues reported that CPB had to be re-instituted, following a severe protamine reaction while during CPB, they were unable to increase arterial pressures even with norepinephrine and had to use an infusion of MB to generate adequate pressures.

Pre-operative useStudy done by Ozal and associates identified 100 patients for

coronary surgery who were at high risk for vasoplegia (preoperative ACE inhibitors, calcium blockers, and heparin) and randomized these patients to receive methylene blue (2 mg/ kg over 30 min) or placebo pre-operatively.

The prophylactic infusion of MB in these patients was associated with a higher SVR during surgery (compared to placebo) and a lower requirement for norepinephrine, inotropic support, fluid and blood transfusions.

While prophylactic MB prevented VS in every patient in whom it was administered, 26% of the patients in the placebo group had VS.

Methylene Blue

Mode of action on vascular smooth muscle: Methylene blue counteracts the effect of NO and other vasodilators on the endothelium and vascular smooth muscle and it is believed to act competitively with NO, by binding to iron heme-moiety of soluble guanylyl cyclase (sGC) and blocking sGC action in vascular smooth muscle alleviates the vasorelaxant effect seen in VS.

Nitric Oxide

•nitric oxide synthase:•A constitutive type •&•An inducible type

Gaunylat

Cyclase

cGMP

• Vascular Dilatation

• Myocardial suppression

IL1 & OFR

•CPB mediated inflammatory response

Gaunylat Cyclase

cGMP • Vascular Dilatation• Myocardial suppression

Vasoplegic Syndrome

Methylen blue

Methylene Blue Dose: Single dose of i.v. MB 1-2mg/Kg over 20 minutes infusion

time as rescue treatment in the setting of vasoplegia post cardiac surgery.

Continuous MB infusion is described in the patient who is not responding to a single dose of MB and is administered for a variable length of time, 120mg MB diluted in D5W given over 1-6 hours .

Methylene Blue has been used in the setting of vasoplegia related to cardiac surgery, sepsis , anaphylaxis, liver failure and hemodialysis .

At higher doses than that described above, MB becomes an oxidant which oxidize hemoglobin resulting in methemoglobinemia and hyperbilirubinemia

Contraindications and side effects of Methylene Blue :

MB should not be used in patients who are hypersensitive to the drug.

Although contraindicated in patients with severe renal insufficiency, it can be used in hemodialysis dependent patients .

MB must be used cautiously in patients with either Glucose-6- Phosphate dehydrogenase deficiency because of the risk of hemolytic anemia .

Rare side effects with high doses include cardiac arrhythmias (nodal rhythm or ventricular ectopy), coronary vasoconstriction, and angina, decreased COP, decreased renal and mesenteric blood flow, increase pulmonary vascular resistance and worsening gas exchange .

Summary as regards Methylene blue

1) In the recommended doses it is safe (the lethal dose is 40 mg/kg);

2) The use of MB did not cause endothelial dysfunction.

3) MB is not a vasoconstrictor, but it facilitate the catecholamine vasoconstrictor effect and eradicate the effect of vasodilatory substances

4) The most used dosage is1- 2 mg/kg as IV bolus followed by the same continuous infusion because plasma concentrations strongly decays in the first 40 minutes.

5) Although there are no definitive multicentric studies, the MB used to treat heart surgery VS, at the present time, is the best, safest and cheapest option, but;

MB ACTION TO TREAT VASOPLEGIC SYNDROME IS TIME-DEPENDENT”.

Other lines of treatment

Fluid resuscitation

IV corticosteroid

Treatment of complication ( MOFS management )

Vasoplegic Syndrome complicating other illness increases management chalanges(diagnosis & treatment )

Vasoplegic syndrome in patient with Vasospastic angina .

Vasoplegic syndrome in patient cardiomyopathic patient with poor EF .

Vasoplegic syndrome in patient ALI & ARDS .

Vasoplegic syndrome in patient Acute right sided failure .

Vasoplegic syndrome in patient AKI.Vasoplegic syndrome in patient with

mechanical circulatory support .

What about our sick patient ??

Day zero Post Operative Optimization of filling pressure with IV fluid.Single bolus dose of M.B 100 mg followed by

infusion for 6 hours beside NEPI & EPI infusion Significant improvement of SVR progressively

increased to 900 - 1300 dynes · sec/cm5 on follow up with MAP 70 to 80

Upgrading of pacing to DDDMechanical Ventilatory management following the

protective lung strategy and titrating PEEP to achieve good O2 saturation

No more ST elevation as if MAP above 70 Sedation/muscle relaxant :Ketamine and

pancuronium Pavulon.Adjusted doses of prophylactic antibiotics

Day one post oprative Better HD profile Better serial ABG Better pulmonary artery catheter hemodynamic

parameters .Bedside ECHO showed good LV function Weaning of IABP then DC .Improvement in laboratory profile Starting Weaning vasopressors and inotropic supports.Better ventilator outcome. Good urine output with good negative balance .

Sternum closed on 3rd day P.O.Patient continued progressive improvement of all

pathological parameters and extubated on 6 th day post operative.

Normalization of laboratory profile follow up.kept transiently on NIV ad CPT due to segmental

lung collapse .Patient discharged from CSICU after total 14 days

to intermediate care unit for 2 days then to regular inpatient section .

Still had intermittent conduction defect so PPM was planned pre discharge .

Infrequent ST elevation on follow up(Prinzmetal's angina ) kept on Ca channel blocker life long

Conclusion

Vasoplegic syndrome occurs in 8—10% of patients following cardiac surgery and is associated with increased morbidity and mortality. In a subset of patients with profound vasodilatation, VS does not response to fluids and conventional vasoconstrictors.

In patients who are catecholamine resistant , the early use of vasopressin is beneficial and in some centers vasopressin is rapidly replacing noradrenaline as the first line treatment for vasoplegic syndrome with consideration of its availability & major side effects .

The inhibition of guanylate cyclase elicited by nitric oxide or any endothelially soluble guanylate cyclase-activating factor (e.g. interleukin-1, atrial natriuretic peptide, and bradykinin) could be a great effective approach in the treatment of norepinephrine-refractory vasoplegia after CPB, and forms the basis for the use of methylene blue.

Conclusion

Methylene blue seems to be a potent approach to norepinephrine refractory vasoplegia with no major side effects. The early use of methylene blue may halt the progression of low SVR even in patients responsive to norepinephrine and mitigate the need for a prolonged vasoconstrictor use.

Preliminary results suggest that pre-operative methylene blue reduces the incidence and severity of vasoplegic syndrome in high-risk patients, thus ensuring adequate SVR intra and post-operatively.

Whether methylene blue should be the first line of therapy in patients with VS is a matter of debate and should be tailored according to the patient statues .

There is inadequate evidence to support its usage as a first line drug, although the promising results of the small number of studies .

On the basis of the current evidence methylene blue does not appear to be the ‘magic bullet’ which need further studies . .

When we are stuck we must make our way of thinking out of the box in a safe

manner