Case Reports in Anesthesia

Blog with interesting cases and/or problems related to anesthesia with discussion based on best evidence in the literature.

January 16, 2020

72 year old male with gastric outlet obstruction

On a Saturday call I was called in to take care of a 72 year old gentleman who had undergone a six hour paraesophageal hernia repair and extensive lysis of adhesions 10 days prior.  He was now suffering from abdominal pain with radiological studies that showed extensive colon dilation with stool and lack of movement from the stomach to the duodenum leading to a diagnosis of gastric outlet obstruction.  The patient had an NG tube in place which was on suction.  The patient was alert and orientated able to answer questions with no signs of obtundation or lethargy.

 Lab values were significant for the following:
  • Sodium level of 150 mmol/L
  • Potassium level of 3.2 mmol/L
  • Chloride of 116 mmol/L
  • BUN of 26.
  • Magnesium level of 1.7 mmol/L
  • Calcium (total) 7.9 mg/dL
  • Phosphate 1.8 mg/dL
  • Creatinine 0.8 mg/dL (down from 2.8  10 days earlier after AKI)
Post op labs
  • Sodium down to 140 mmol/L
  • Potassium level increased to 4 mmol/L
  • Chloride slightly decreased to 114 mmol/L
  • BUN  of 25
  • creatinine 1.2 mg/dL
  • Magnesium of 1.6 mmol/l
  • Calcium 7.4 mg/dL
  • Phosphate 4.0 mg/dL

Gastric outlet obstruction is typically considered a medical emergency not a surgical emergency as serious electrolyte abnormalities are typical along with significant alkalosis if not treated.  The standard textbook presentation of gastric outlet obstruction (GOO), is a dehydrated patient with a metabolic alkalosis, hypochloremia, hypokalemia and hyponatremia.  Initially, the kidneys will dump bicarbonate into the urine to avoid serious alkalosis and retain chloride ions. However, this process is overwhelmed as dehydration ensues.  At this point, the kidneys agressively attempt to retain fluid by holding onto sodium at the expense of secreting potassium and hydrogen ions.  This leads to a paradoxical acidic urine and further exacerbates the alkalemia and hypokalemia.  Alkalosis leads to a reduction in circulating calcium levels. This patient, despite a diagnosis of GOO, did not have the typical biochemical abnormalities associated with this syndrome.

  Firstly the patient had significant hypernatremia (Na greater than 144 mmol/L).  Clinically, the sensation of intense thirst that protects against severe hypernatremia in health may be absent or reduced in patients with altered mental status or with hypothalamic lesions affecting their sense of thirst and in infants and elderly people. Non-specific symptoms such as anorexia, muscle weakness, restlessness, nausea, and vomiting tend to occur early. More serious signs follow, with altered mental status, lethargy, irritability, stupor, and coma. Patients with chronic hypernatremia (hyperosmolar states) have adapted their brains via "idiogenic osmoles" to avoid neuronal shrinkage.  Idiogenic osmoles are organic molecules such as myo-inositol, taurine, glycerylphosphorylcholine, and betaine which are accumulated via extracellular fluid uptake via activation of sodium-dependent cotransporters.  Because of this adaptation to chronic hypernatremia, rapid correction of the free water deficit would result in rapid cerebral edema due to the relative hyperosmolarity inside the neuron.
In a systematic review, hypernatremia has been found to be associated with increased 30 day mortality and morbidity [1]. Hypernatremia may result in severe metabolic derangements, myocardial depression and injury, neurologic impairment, venous thromboembolism, and poor wound healing. Although there is an association, it is not proven that preoperative treatment of hypernatremia will improve outcome.  It is clear that the rate of change in sodioum levels is very important.  One study showed that slow rates of improvement (less than 0.25 mmol/L/hr) were typically inadequate with a 3-fold increased risk of 30 day mortality compared to those with a more rapid rate of correction (0.25 to 0.5 mmol/L/hr).


The most likely reason for this patient's hypernatremia was loss of hypotonic body fluids with addition of hypertonic TPN. Rapid and aggressive fluid volume replacement should have been started immediately to correct his likely volume deficit.    Also, the free water deficit needed to be replaced.  The formula to determine the free water deficit (L)=[0.6 x IBW] x [(current [Na+]/140)-1]. The deficit should be corrected in the short term by 1/2 or 50% of the deficit with the remainder corrected over the next 24 to 36 hours to minimize cerebral edema.

Therefore, in my patient, his estimated free water deficit at the start of the case was (in liters): 0.6 x 70kg= 42 x (150/140)-1 = 2.99 L.   During the case in order to avoid truly catastrophic cerebral edema while under GETA, I planned a very mild correction and estimated that slowly infusing 1/2 NS would help provide a small amout of free water while volume ressuscitation for the case with some 5% albumin (250 mL) and LR (3.5 L).  LR contains 130 mEq/L of sodium, 4 mEq/L of potassium, 2.7 mEq/L of Calcium, 109 mEq/L of Chloride and finally lactate 28 mEq/L.

The Adrogue Formula will allow you to determine how much the serum sodium level will change based on the fluid you infuse:  Change in serum Na+= (infused Na+ - serum Na+)/(TBW +1).  For my patient using 1/2 NS and plugging in the data, the expected change in serum sodium after the six hour case was (75 - 150)/(0.6 x 70kg)+1 = 1.74 mmol.  If my target is to reduce the serum sodium by about 0.3 mmol/hr, after 6 hours (approximate length of the case), I would want to have reduced the serum from 150 mmol/L to 148.2 mmol/L.  It turns out that I didn't use the above formulas, nor make the calculations listed above. I guestimated that giving 1 L of 1/2 NS would be safe and help reduce to some degree the amount of hypernatremia.  It turns out that the 1 L of 1/2 NS I infused over the six hour procedure was predicted to reduce the serum sodium by 1.74 mmol/L and my goal based on the above equations was to decrease it by 1.8 mmol after six hours.
In retrospect, I do not believe the goal should be focused at all on reducing serum sodium when taking a patient with chronic hypernatremia who is not suffering any symptoms, into major abdominal surgery.  This was likely an error of judgement on my part.

In fact, the patient also had LR infusing, and this was contributing to the reduction in Na+ as well.  I infused 3.5 L of LR and the estimated reduction in serum sodium from this therapy would be (130-150)/42+1 =  0.46 mmol/L x 3.5 L = 1.62 mmol total. This shows that I actually overshot my goal by using LR aggressively during the case. Therefore, when facing a patient with likely chronic hypernatremia undergoing major abdominal surgery, the best therapy is to use LR as needed.

My patient also suffered from hypomagnesemia. Magnesium (Mg2+) plays a major role in a number of pathways in the human body including serving as a co factor for a number of processes (i.e. protein synthesis, neuromuscular function etc.), is an endogenous regulator of several electrolytes, in particular it is a  calcium channel antagonist. In addition, Mg2+ is important in maintaining Calcium levels because low levels of Mg2+ result in end organ resistance to parathyroid hormone and in parathyroid secretion.  Furthermore, Mg2+ also modulates sodium and potassium currents thus affecting membrane potentials.  In the CNS, Mg2+ exerts depressant effects by antagonizing the NMDA receptor and also inhibiting catecholamine release.

Magnesium levels are primarily affected in the small bowel via absorption (passive and active transport) and re absorption in the thick ascending limb of the loop of henle.
Hypomagnesemia results mainly from inadequate dietary intake and/or GI and renal losses.  Hypomagnesemia is often associated with diarrhea, vomiting, use of loop and thiazide diuretics, ACE inhibitors, cisplatin, aminoglycosides,or other nephrotoxic drugs, and several endocrine like parathyroid diseases, hyperaldosteronism, and chronic alcoholism.  In addition, during major abdominal surgery, intraoperative crystalloid infusion may lead to a decrease in the passive magnesium transport, thus leading to a decrease in plasma magnesium concentrations.  The incidence of hypomagnesemia is as high as 65% for patients in the ICU, where hypoalbuminemia, TPN, and the use of magnesium-wasting medications are commonly present.  Patients with head injuries also seem to be at high risk for hypomagnesemia secondary to polyuria.  Hypokalemia and hypocalcemia are also frequently associated with hypomagnesemia.
There has been an effort to associate hypomagnesemia with increased mortality. Several studies have been able to link the two, however, careful analysis and high quality studies have suggested that hypomagnesemia may be an epiphenomenon of critically ill patients who suffer increased mortality.  Therefore, treating low magnesium levels is not likely to reduce mortality.  However, replenishing magnesium levels in surgical patients can have other benefits.  For example, reduction in cardiac dysrhythmias, primary atrial tachyarrhythmias, reduced anesthetic need (MgSO4 as an adjunct anesthetic/analgesic) inhibition of platelet dependent thrombosis, attenuate adverse cardiovascular effects during laryngoscopy, and intubation.  The treatment of hypomagnesemia takes several days of IV therapy because nearly all magnesium is intracellular.  In fact, in critically ill patients, 4 to 6 grams of IV Magnesium per day will likely be required to maintain a serum magnesium level of near 2 Gm/dL. In addition, IV magnesium can take up to 48 hours to redistribute into the cells, causing serum levels after IV administration to falsely elevated.

The patient was also suffering from hypophosphatemia.  Hypophosphatemia is a very common disorder in critically ill patients occurring in up to 100% of patients in some studies.  Particularly relevant to this patient, TPN can result in sudden and profound hypophosphatemia.  This usually is due to providing TPN to patients who are malnourished, have initial low phosphate levels and then suddenly receive glucose via TPN which supports a sudden increase in the formation of ATP.  With TPN initiation, a sudden acute rise in glucose transport across cell membranes occurs accompanied by oxidative phosphorylation resulting in a large demand on intracellular phosphate for support of ATP production.  This results in "refeeding syndrome" where rapid changes in fluids and electrolytes occurs.  Commonly, this changes result in hypophosphatemia, hypomagnesemia and hypokalemia.  Low phosphate levels can have wide ranging clinical effects including myocardial dysfunction, diaphragmatic weakness, seizures, coma, rhabdomyolysis, and red blood cell dysfunction from tissue hypoxia (by decreased RBC 2,3-DPG).  Furthermore, there is some evidence that hypophasphatemia is associated with longer ICU and hospital stays and increased risk of arrythmias. A recent retrospective analysis found that hypophosphatemia was associated with increased 28 day mortality in the ICU [2].  The authors of this study concluded based on their analysis that independent of illness severity, hypophosphatemia still resulted in increased mortality. This patient had significant hypophosphatemia, and I elected to replace phosphate during the case.  It is important to consider the calcium levels of patients who receive phosphate repletion because the calcium level will likely decrease as phosphate is replaced.
My patient went to the ICU intubated post op.  No problems were evident related to his severe electrolyte abnormalities.  He required prolonged post operative care in the ICU with mechanical ventilation. However, after about two weeks he was extubated and made progress.

Memorizing the dosing of all electrolyte replacements is tedious and unnecessary. I have included a simple calculator that can be stored on one's home screen of their smart phone for easy use to determine the appropriate dose to give a patient assuming IV administration.

Lyte Calculator






1.  Leung AA, McAlister FA, et al. Amer J Medicine. V. 126(10): 2013. p 877-885
2. Wang L, Xiao C, Chen L, Zhang X, Kou Q. BMC Anesthesiology. 86;2019.

August 21, 2019

Post op MI after lap h/h repair

A 61 year old mail presented for repair of a hiatal hernia for symptomatic GERD via a laparoscopic approach and LINX placement.  The patient had a history of HTN, hyperlipidemia and CAD with stents placed in 2013 and 2016.  He was no longer on any anticoagulants and had a negative stress test 9 months previous.  The patient stated that he was in his usual state of health at the time of surgery with no chest pain, limitations of activity due to shortness of breath, or otherwise.  The patient was otherwise active capable of doing more than 4 METS of work.

The patient was induced in the usual fashion and provided GETA with desflurane.  The anesthetic was complicated by severe hypotension and bradycardia when placed in reverse T-burg at the beginning of the case which was treated with glycopyrrolate (0.2mg) and ephedrine 15mg in 5 mg increments.  Aproximately 45 min into the case the patient developed tachycardia of 109 or so BPM and this was treated with a bolus of 100 mcg fentanyl and esmolol 30 mg.  Towards the end of the case the patient developed significant hypotension again and this was treated with a very small dose of phenyephrine given via slow drip.

The surgical time was a little over one hour. The patient emerged from anesthesia without complications, was extubated in the OR and taken to PACU in excellent condition. The patient appeared comfortable and care was transferred to the PACU nurse.  After approximately 30 min I went back to see how the patient was doing.  He appeared comfortable, sleeping in bed.  I finished my paper work and signed out to the nurse and headed for the door.  About 10 min later as I had just pulled out of the facility I was called by the nurse stating that the patient was having chest pain and his EKG tracing appeared abnormal.  The nurse told me she had already ordered and EKG.  I asked her to call me with results.  I was called about 5 min later by a panicked nurse stating the patient's EKG showed a STEMI.  The ER doc had already been called and given them orders to begin a code STEMI. Patient was transferred to a nearby hospital for further care where an occluded stent was encountered and treated with stenting.
This is a picture of the patients lesion prior to a stent being placed.

This patient had an acute coronary syndrome (ACS) further specified as ST segment elevation myocardial infarction.  There are two other ACS subtypes, non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina.

  1. Unstable angina-New onset chest pain that is cardiac in nature or chest pain that is getting progressively worse without any elevation in cardiac specific enzymes.
  2. NSTEMI-EKG changes consistent with ischemia, and elevation in cardiac specific enzymes indicating myocardial damage.
  3. STEMI-EKG changes where at least a 1 mm elevation in the ST segment is encountered that is new and associated with elevation in cardiac specific enzymes and should be in contiguous leads.
The patient in this case report complained of chest pain. Unfortunately, 100% of patients experience chest pressure and pain after lapx hiatal hernia repair. So this complaint is non specific.





In our case, we had ST elevation in the septal, anterior and lateral leads.

  • Septal leads (V1/V2)
  • Anterior leads (V3/V4)
  • Lateral leads (V5/V6)
(sample)

Above is an example of anterolateral STEMI with some septal involvement (V2).

Post op MI tends to occur early-see below. 
  • 44% day of surgery
  • 34% POD 1
  • 16% POD 2



Prior to surgery, the risk for a major adverse cardiac event (MACE) in this patient can be estimated using the revised cardiac risk index (RCRI):
  1. high risk surgery = 1 pt
  2. Ischemic heart disease (coronary artery disease) = 1 pt
  3. history of congestive heart failure = 1 point
  4. history of cerebral vascular disease (h/o of CVA or TIA) = 1 pt
  5. diabetes requiring insulin treatment = 1 pt
  6. preoperative creatinine greater than 2 mg/dl = 1 pt

This patient had one risk factor  (ischemic heart disease) on the RCRI scale and therefore, was awarded 1 point. Therefore, the patient's risk for major cardiac morbidity would be  0.9% (see here):  0 – 0.4%     1 – 0.9%      2 – 6.6%        3 or more – 11%


The RCRI has a moderately good ability to discriminate patients who will develop cardiac events from those who will not after mixed noncardiac surgical procedures (area under the curve [AUC] 0.75), it is less accurate in patients undergoing vascular surgical procedures (AUC, 0.64), and it is less able to predict all-cause mortality (median AUC, 0.62). Recently a published geriatric sensitive RCRI performed better on patients over age 65 than the original RCRI [2].

To overcome these limitations of RCRI, the National Surgical Quality Improvement Program (NSQIP) score was developed and validated on 211,410 surgical patients. This model includes age, ASA class, functional status, abnormal serum creatinine, and a novel and more appropriate organ-based categorization of surgery. Risk may be quantified by a risk calculator on the Internet. The discriminative or predictive ability of the NSQIP score is significantly better as compared with RCRI (AUC, 0.88), and it works well also in vascular surgical patients.  The NSQIP calculator is very labor intensive making it somewhat impractical to use by the bedside clinician.  However, I input the data from this case into the   online calculator available for free. The result indicated that the patient was at less than 1 % risk for cardiovascular complications.

The preop EKG in patient's with cardiac disease

ECG abnormalities are not part of either the revised cardiac risk index (RCRI) or the National Surgical Quality Improvement Plan (NSQIP) because of the lack of prognostic specificity associated with these findings.

The rationale for obtaining a preoperative ECG comes from the utility of having a baseline ECG should a postoperative ECG be abnormal.

Subjective assessment of cardiopulmonary reserve (i.e. evaluation of METs) prior to surgery suffers from poor sensitivity (i.e. falsely labels high risk patients as low risk).  Therefore, in patients with more than 4 METs where there is an otherwise high index of suspicion for disease, a low threshold for further evaluation should exist.  On the other hand, patients with a low MET score (i.e. inability to engage in activities equivalent to at least 4 METs) is very good at predicting a patient at higher risk. However, this method is also not used in the formal scoring systems for predicting post operative cardiac risk.

According to the recent ACC/AHA guidelines, stress testing is not indicated unless it would be done regardless of the planned surgery. In addition, resting echocardiography is not indicated unless needed regardless of planned surgery to evaluate ongoing dyspnea or evaluate valve function in a patient with a murmur.

On UpToDate, a summary of the preoperative approach to cardiac evaluation includes the following general principles:
  • All patients scheduled to undergo noncardiac surgery should have an assessment of the risk of a cardiovascular perioperative cardiac event  and the patient’s functional status is an important determinant of risk. 
We use either the revised cardiac risk index (RCRI), also referred to as the Lee index, or the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk prediction rule to establish the patient’s risk. 
We obtain an electrocardiogram (ECG) in patients with cardiac disease (except in those undergoing low-risk surgery) in large part to have a baseline available should a postoperative test be abnormal.
For patients with known or suspected heart disease we only perform further cardiac evaluation (echocardiography, stress testing, or 24-hour ambulatory monitoring) if it is indicated in the absence of proposed surgery.

In a 2007 study, it was found that the only preoperative EKG abnormality that was predictive of post op MI was a bundle branch block (right or left).  However, this abnormality did not improve prediction beyond risk factors identified in patient history.

In the immediate post operative period anticoagulation may be contraindicated for treatment of ACS. 

There are two main types of MI that anesthesiologists are likely to encounter in the preoperative period: Type I MI and Type II MI.  A type I MI occurs when a thrombus forms with a plaque rupture in a coronary artery  and causes acute obstruction to blood flow. Type II MI occurs when there is a demand supply imbalance of oxygen. In general, the literature suggests that both types can occur in the preoperative period with a frequency that varies largely based on the reference study.  In one angiographic study, nearly 50 percent of patients with perioperative acute coronary syndrome had evidence of plaque rupture [3]. However, in this case presentation, the patient had what could be called a type 4b MI (stent thrombosis). In a recent retrospective study, Helwani et al. [1], showed that 72% of post operative MIs were Type II, while 25% were of type I (acute plaque rupture). They also found an event rate of 2.1% for type 4b (stent thrombosis).  






Type 4b MI, or stent thrombosis, is a greater risk shortly after stent placement.  Recommendations currently state that dual antiplately therapy should continue for 30 to 45 days after a bare metal stent because the stent undergoes reendothelialization quickly.  In the updated guidelines of 2016, the period of mandatory DAPT after a second generation DES has been shortened to six months for patients with stable CAD.   These second generation DES appear to be much safer when it comes to stent thrombosis. Even newer DES are pushing the window back even further to only 1 month. However, experts are recommending that aspirin therapy be continued into the operative period whenever possible.  The last time a stent had been placed in the above patient was 2016 and therefore, the patient was not required to continue DAPT during the surgical period.

Mortality from myocardial infarction (MI) after noncardiac surgery[] is believed to be 10 to 15%. High-risk patients experience perioperative MI 3.0% of the time.

Once a diagnosis is made management consists of the following general themes:

  • Antiplatelet agents-ASA, plavix, GP IIb/IIIa inhibitors
  • Anticoagulation-Heparin, LMWH, Fondaparinux, Bivalirudin
  • Anti ischemic therapy-B blockers, nitrates, CCB
  • Statins
  • Ace inhibitors
  • O2*
  • Transfusion as needed
* There is some evidence that hyperoxia in patients with STEMI may not be beneficial, but rather harmful [3]. In an RCT, patients given supplemental oxygen in the prehospital treatment of STEMI, had an increase in infarct size at six months after diagnosis of MI.

In the PACU, the patient was given IV heparin 1000 units, nitroglycerine infusion for elevated blood pressure, and aspirin to chew (325mg).  The treatment of ACS with ST elevation generally includes immediate (less than 2 hours) cardiology consultation for PCI, which is what occurred with my patient. A stent was placed and the patient was discharged home on POD #2 in good condition.

Lastly, in patients who are considered at risk of MACE in the perioperative period, it might make sense to use a volatile anesthetic as the major component of anesthesia due to the proven ability of these agents to condition cardiomyocytes (as well as neurons) against ischemic damage.  The mechanisms behind anesthetic preconditioning relate to reduction in inflammation, cytokines, and a cascade of enzymes that prevent ischemic reperfusion damage.



 A meta-analysis of randomized clinical trials involving 1922 patients undergoing cardiac surgery showed that, in comparison with total intravenous anesthesia (TIVA), desflurane and sevoflurane achieved significant reductions of myocardial infarctions [2.4% in the VA group vs 5.1% in the TIVA group, odds ratio (OR) 0.51] and all-cause mortality (0.4% vs 1.6%, OR 0.31) [4].  Furthermore, an international consensus conference provided expert opinion support for the use of VA in hemodynamically stable cardiac surgery patients [5] as a means to reduce myocardial damage and death. The pre conditioning affect appears to be dose dependent, and benefits are typical found at a usual clinical dose of 1 MAC.

This case highlights that patient coming to surgery with apparent low risk (RCRI of 1 pt = 0.9% risk of MACE) are still vulnerable and a high index of suspicion is required so that if a MI type 4b occurs, rapid transfer to the cath lab will occur for definitive therapy. Anesthesiologists need to be aware of and ready to institute the first line of therapy in preparation for PCI which includes beta blockade, anti platelet agents (asa), nitro as tolerated and pain control with morphine or an equivalent.






1. Helwani, MA, Amin, A, Lavigne, P, Rao, S, Oesterreich, S, Samaha, E, Brown, JC, Nagele, P Etiology of acute coronary syndrome after noncardiac surgery. Anesthesiology 2018; 128:1084–91

2. Alrezk R, Jackson N, Al Rezk M, Elashoff R, Weintraub N, Elashoff D, Fonarow GC: J Am Heart Assoc. 2017;6:e006648


3. D. Stub, K. Smith, S. Bernard, Z. Nehme, M. Stephenson, J.E. Bray, et al., Air versus ox- ygen in ST-segment-elevation myocardial infarction, Circulation 131 (2015) 2143–2150.


4.   Landoni G, Biondi-Zoccai GG, Zangrillo A, Bignami E, D'Avolio S, Marchetti C, Calabrò MG, Fochi O, Guarracino F, Tritapepe L, De Hert S, Torri G. J Cardiothorac Vasc Anesth. 2007 Aug; 21(4):502-11.

5 .Landoni G, Augoustides JG, Guarracino F, Santini F, Ponschab M, Pasero D, Rodseth RN, Biondi-Zoccai G, Silvay G, Salvi L, Camporesi E, Comis M, Conte M, Bevilacqua S, Cabrini L, Cariello C, Caramelli F, De Santis V, Del Sarto P, Dini D, Forti A, Galdieri N, Giordano G, Gottin L, Greco M, Maglioni E, Mantovani L, Manzato A, Meli M, Paternoster G: Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference. Acta Anaesthesiol Scand. 2011, 55 (3): 259-266.







March 10, 2019

5,10 methylenetetrahydrofolate reductase deficiency in my patient

This past month I have suddenly had two teenagers present for surgery claiming to have 5,10 methylenetetrahydrolate reductase deficiency.  Ironically, I had just reviewed two articles on this exact issue in my past journals of anesthesiology.  This was nice, because it allowed me to offer a degree of comfort to the patients by appearing to be informed of the disease and potential pitfalls.   What made me particularly interested in doing a write up about this particular genetic polymorphism was that the mother of the second patient gave me a paper claiming that these patients should avoid propofol, epinephrine, lactated ringers, and N20. (here is the link) The mother was hyper anxious and emotionally charged in discussing the anesthetic.  She appeared ready to defend her position and stated that her daughter had an "allergy" to propofol and lactated ringers.  I reassured her that it would be no problem to avoid propofol and nitrous oxide for her anesthetic and the mother appeared to back down in a somewhat disappointed manner as if she was hoping for more push back from the doctor which could provide her an opportunity to demonstrate to her other family members her superior intellect.  However, I was intrigued enough to spend some time looking at the anesthetic literature related to this deficiency to better understand how propofol, bupivacaine, lactated ringers or epinephrine might have been included in the list of things to avoid by this very concerned mother.

In general, the main concern related to 5,10 methylenetetrahydrofolate reductase (MTHFR) deficiency is related to increased homocysteine in the blood.  Homocysteine is an amino acid that has been associated with increased cardiovascular disease.  In a large cohort [4] of (~18,000 men and woman) in western Norway, total plasma homocysteine was associated with increased risk of cardiovascular morbidity, general mortality, and depression with neurocognitive deficits in the elderly.  This cohort study, demonstrated an association, but cannot be said to prove that elevated total plasma homocysteine caused these outcomes.  However, other case control studies have also found an association with elevated plasma homocysteine levels and increased vascular disease. Graham IM et al. showed in a case control study that increased plasma total homocysteine levels is an independent risk factor for vascular diseases similar to that conferred from smoking or hyperlipidemia.  It also was shown to powerfully increase the already elevated risk associated with smoking and hypertension [5].  It is estimated that plasma levels above 10 micromol/L are associated with a doubling of vascular risk and levels greater than 20 micromol/L can confer a TEN fold increased risk of vascular disease.  Furthermore, acute increases have also been shown to cause endothelial dysfunction and provide procoagulant effects [6]. Chambers et al. hypothesize that hypomethylation is the major biochemical mechanism in homocystinemia vascular disease in addition to inhibition of HDL biosynthesis in humans.

Hyperhomocysteinemia can result from a number of causes.  These include vitamin deficiencies such as Vitamin B6 (pyridoxine), Vitamin B12, and folic acid.  Renal insuficiency can also be a culprit.  Genetic defects that are relevant to homocysteine levels and anesthesia practice include methyltetrahydrofolate reductase deficiency and cystathionine β synthase deficiency. 

Cystanthionine β Synthase deficiency is a congenital disorder that is also known as homocystinuria and is associated with defects in collagen such that patients suffer from a marfanoid like body with defects in bone and issues with the eyes.  They are prone to hypoglycemia, therefore, patients having surgery will require short fasting periods and supplementation during fasting with IV dextrose. Furthermore, thromboembolic complications are high and measures must be taken to reduce these complications in the perioperative period.

Acute increases in homocysteine were found to occur in patients given nitrous oxide. These acute increases of homocysteine levels were associated with cardiovascular damage in a 2000 clinical study.  Badner et al [7] looked at  patients undergoing carotid endarterectomy  who were randomized to a nitrous oxide(N2O) group (more than 50%) vs. no nitrous. They found that in those receiving N2O, homocysteine levels were significantly increased from an average baseline of 12.7 μmol/L to 15.5 μmol/L in the PACU. Although, this was a very slight increase, it was statistically greater than the non N2O group.  Furthermore, this resulted in patients in the N2O group experiencing more frequent episodes of ischemia in the first 48 hours post op and a longer average duration of ischemia post op.  There was no increased cardiovascular morbidity noted although this wasn't an end point of the study. Importantly, they found that the univariate predictors of myocardial ischemia in these patients were N2O use (RR 1.9), homocysteine greater than 17 μmol (RR 2.0), and  pre and intraop ischemia (RR 3.7). These same authors noted that the potential causes of elevated ischemic risk in the patients with elevated homocysteine can be traced back to homocyteine's effects on the vascular endothelial lining and known procoagulant effects such as increased platelet adhesivness, factor V activation, protein C inhibition and antithrombin and plasminogen activator binding. It is likely that these effects are mediated by the consumption of nitric oxide (potent vasodilator).

N2O inhibits vitamin B12 (cobalamin) by irreversibly oxidizing the cobalt atom (from +1 to +3 valence state) of cobalamin. This leads to subsequent inhibition of enzymes requiring cobalamin in its coenzyme form. Because this is an irreversible inhibition, the reduction of cobalamin lasts several days.  Among the many enzymes, methionine synthase is crucial because it's located at the juncture of two pathways: homocysteine remethylation and the folate cycle. (fee fig)

fig (see reference 8.)

Therefore, when cobalamin is oxidized via N2O, homocysteine can no longer be converted into methionine and builds up in the blood.  As noted in the above chart, a multitude of problems can now arise, because purines, thymidine, and RNA/DNA methylation all depend on the proper function of this pathway (see fig).  In particular, S-adenosylmethionine (from methionine) is critical in the methylation of myelin sheath phospholipids resulting in decreased myelin formation. Furthermore, elevated homocysteine levels are thought to lead to increased concentrations of S-adenosyl homocysteine (SAH), a feedback inhibitor of methylation reactions. In this case, patients with severe vitamin B12 deficiency exposed to nitrous oxide are at particular risk of subacute combined degeneration of the spinal cord. Degeneration in the spinal cord occurs primarily in the posterior and lateral columns, but can in rare occasions occur in peripheral nerves and white matter in the brain. There have been a number of case reports related to this in susceptible individuals in the literature. In general, patients in the case reports are found to 1) be deficient in vitamin B12, or 2) abuse N2O.  Patients present from days  to weeks after an exposure to N2O with ataxia, sensory deficits that are symmetrical, with deficitis of propioception and vibration sensory discrimination (posterior columns). These patients often have a megalobastic anemia (or no anemia, but elevated MCV) which goes along with vitaminB12 defiency. In severe cases, death or permanent disability are the result. In many cases, high doses of vitamin B12 can result in a resolution.

The methylenetetrahydrofolate reductase gene (see fig above) (MTHFR) has two distinct polymorphisms that result in deficits and have a combined prevalence of 20% in the Western European population.    Two prominent case reports [9,10] related these polymorphisms to catastrophic neurologic outcomes in children which have lead to further studies being conducted.  In a 2008 study, [8], 140 healthy patients were carefully evaluated to determine how the above two polymorphisms affected homocysteine levels after N2O (66%) anesthesia. They found significantly higher homocysteine levels in patients who were homozygous for MTHFR 677T or MTHFR 1298C (5.6 increase vs. 1.8 μM)

Fig. 2. Plasma homocysteine concentrations in the different groups based on methylenetetrahydrofolate reductase (  MTHFR  ) 677/1298 genotype at three different time points: preoperative, after 2 h of anesthesia, and at the end of surgery. Both homozygous groups developed significantly higher homocysteine concentrations than the other groups (***  P  < 0.001). Genotype combinations (  MTHFR  677/1298): wt/wt: CC/AA; het/wt: CT/AA; wt/het: CC/AC; het/het: CT/AC; wt/hom: CC/CC; hom/wt: TT/AA

This same study was also able to show that even in patients with normal genetic (wild type) function at the MTHFR locus, prolonged (greater than four hours) exposure to N2O could substantially increase homocysteine levels.  In this group of patients with prolonged exposure, there was an approximate 80% increase in homocysteine levels which is similar to the increase experienced by those with the shorter exposures but homozygous for MTHFR polymorphisms.

More recently, a study of pediatric patients was conducted who had known MTHFR deficiency.  In this cohort, they found 12 patients with known MTHFR defiency (ages 3.5 months to 9 years).  All twelve patients had normal homocysteine levels preoperatively.  The authors found no increase in homocysteine levels in these twelve at risk patients.  Four of the twelve had a TIVA with propofol and the remainder underwent sevoflurane anesthesia.  Nitrous oxide was avoided in all twelve. Although this study seems to suggest that in healthy pediatric patients with MTHFR deficiency, anesthesia is safe and homocysteine levels are not increased, there are reports of morbidity from MTHFR deficiency after "safe" no nitrous anesthesia. A case report from 2007 describes a patient who underwent urgent surgery with a preoperative diagnosis of homogyzous MTHFR deficiency. The patient was apparently well managed with coumadin and folic acid for prevention of ischemic insults. In the post operative period this patient developed a coronary ischemic insult and renal artery thrombosis [11].

Finally, there is evidence to suggest that despite acute elevations in homocysteine with adminstration of N2O, it may not be clinically relevant.  In 2013, Nagele et al. published results in Anesthesiology  [13], showing that even in patients with with at least two cardiovascular risk factors AND being homozygous for MTHFR deficiency, there was no difference in increase in Troponin I increases for 72 hours post operatively.  They did find that patients homozygous for MTHFR deficiency had an increase in post operative homocysteine as has been previously shown.  There were two arms of randomization (n=250) in patients determined to be homozygeous for MTHFR deficiency.  One arm received 1mg vitamin B12 and 5 mg folic acid (before and after surgery) and the other arm received a saline placebo. All patients received a balanced anesthetic with 60% nitrous oxide for procedures lasting at least two hours. The results indicated that although vitamin supplementation did lower homocysteine levels,the incidence of elevation of troponin I was not different between groups.

This study provided further evidence that N2O results in an increase in homocysteine plasma levels and that these levels can be decreased by vitamin B12 supplementation.  However, the study may have diminished  concerns that an acute elevation of homocysteine levels after a short interval of anesthesia (~2 hrs) will lead to myocardial damage. The authors noted that there is a growing consensus that homocysteine may be a marker, rather than a cause of atherosclerotic disease and increased cardiovascular risk.  The authors also noted that in this study, N2O did not result in an increase in homocysteine to a greater degree in MTHFR homozygous patients vs wild type genotype.  They concluded that this difference was related to national mandatory folate fortification of all grain products in the US which can reduce the effects of MTHFR polymorphisms.  This is in contrast to the study population in an earlier study conducted in Austria, a country without mandatory folate fortification.

In my case, I was presented with documentation by the mother that she apparently obtained from the web that indicated that I needed to avoid propofol, lactated ringers, bupivacaine and epinephrine in order to provide safe anesthesia. It is clear, after consulting the literature and gaining a greater understanding of the biochemicals pathways involved in MTHFR deficiency, that propofol, lactated ringers and epinephrine would not increase risk.   It seems clear after reading the report that the authors seemed to have conflated MTHFR deficiency and a general mitochondrial disease. Indeed, there are a number of different congenital mitochondrial diseases and depending on the type encountered, propfol, lactated ringers, bupivacaine and epinephrine may be a relative contraindication. Mitochondrial diseases can be broken down into two major groups of related diseases. These are defects of the respiratory chain and defects in fatty acid transfer and metabolism. Propofol may have been on the list due to its relation to propofol infusion syndrome (PRIS) which leads to mitochondrial dysfunction and lactic acidosis.  In fact, propofol is unque among parenteral anesthetics in that it is known to affect mitochondrial metabolism by at least four separate mechanisms. It can uncouple oxidative phosphorylation and inhibit complexes I, II, and IV.  However the strongest effect of propofol is its inhibition of transport of long-chain acylcarnitine esters via inhibition of acylcarnitine transferase (carnitine palmitoyl transferease I). However, reveiws note that even in patients with mitochondrial defects, a limited one time bolus of propofol for induction of anesthesia seem generally well tolerated. The number and manifestations of mitochondrial disease are enormous and protean. Fortunately, MTHFR is not related to the function of the mitochondria and even patients homozygous for the defective gene of this enzyme seem to tolerate anesthesia without significant complications, even when given nitrous oxide. Now, I feel I would be better equipped to have a more involved and informative conversation with the mother. This will allow to me to push to maintain the freedom to use propofol, bupivacaine, LR, and epinephrine if I feel that they would be important to use.








1. Shay H, Frumento RJ, Bastien A. J Anesth. 2007;21:493–6.
2.  Badner NH, Beattie WS, Freeman D, Spence JD. Anesth Analg2000;91:1073–9
3. Nur Orhon Z, Koltka EN, Tufekci S, Buldag C, Kisa A, Durakbasa CU, and Celik M. Turk, J Anaesthesiol Reanim. 2017;45(5):277-281.
4. Ueland, PM, Nygard, O, Vollset, SE, Refsum, H 2001The Hordaland Homocysteine Studies Lipids.  2001; 36S33-S39
5. Graham IM, Daly LE, Refsum HM, et al. JAMA. 1997;277:1775-81.
6.  Chambers JC, McGregor A, Jean-Marie J, Kooner JS. Lancet. 1998;351:36-7.
7. badner NH, Beattie WS, Freeman D and Spence JD. Anesth Analg.                     2000; 91:1073-9.
8.  Nagele P, Zeugswetter B, Wiener C, Burger H, Hupfl M. Anesthesiology. 2008;109:36-43.
9. Lacassie HJ, Nazar C, Yonish B, Sandoval P, Muir HA, Mellado P:  Br J Anaesth 2006; 96:222–5
10. Lacassie, HJ Nazar, C Yonish, B Sandoval, P Muir, HA Mellado, P
Selzer RR, Rosenblatt DS, Laxova R, Hogan K: . N Engl J Med 2003; 349:45–50
11. Shay H, Frumento RJ, Bastien J Anesth. 2007; 21(4):493-6.
12.  Badner NH, Freeman D, Spence JD. Preoperative Anesth Analg. 2001;93:1507–10.
13. Nagele P, Brown F, Francis A, Scott M, Gage BF, Miller JP. Anesthesiology.  2013;119:19-28.
14. Hsieh VC, Krane EJ, Morgan PG. Jour inborn Error Metabolism & Screening. 2017;5:1-5.

March 1, 2019

fluid resuscitation in an open bowel resection

61 year old male presents with perforation of sigmoid colon secondary to diverticulitis


On my saturday call, a 61 year old male presented after several days on the floor for open sigmoid colectomy secondary to a perforation of the large bowel.  Versed and fentanyl were given in preparation to go to the OR.  The patient was otherwise stable and talkative in the preoperative area.  After 2mg of versed and 100 mcg of fentanyl, the patient was more somnolent than expected for the given dose.  The patient had a history of coronary artery disease. A review of his cardiac history revealed that he had had an angioplasty nearly 10 years ago with a repeat angiogram eight years ago. His repeat angiogram revealed restenosis of his RCA lesion now occluded at 30 to 40%.  The patient had disease of two other coronary arteries as well.  The patient was receiving nitrates to control angina.  He reported that he was currently asymptomatic.  He was a diabetic using insulin.  He also admitted to drinking vodka each day. Based on this history his RCRI would be 3 pts (1 pt for ischemic cardiac disease, 1 pt for diabetes requiring insulin and 1 pt for high risk surgery ).  By using this tool located here you can derive his preoperative expected risk of major cardiac event at 15%. 

Induction was with 50 mg of propofol and succinylcholine with rapid sequence intubation. His abdomen was very distended and appeared to have ascites.  After intubation, a right radial arterial line was placed.  Blood pressure was stable with induction, however, very shortly after beginning the inhalation agent, the blood pressure dropped down into the 60's systolic.  A phenylephrine drip was begun while decreasing the concentration of desflurane.  A foley catheter was placed, however, no urine returned into the foley bag.  I also noticed that the pulse pressure was large, with very low diastolic pressures (consistently in the 40's).  

Trying to determine the volume status of this patient was a challenge.  The blood pressure was low, and required ongoing low dose phenylephrine as an infusion. The main question thus became, what was the main etiology of this patient's continued hypotension. Vasoplegia secondary to sepsis syndrome, hypovolemia from capillary leak, and inadequate cardiac contractility were all possibilities. Determining fluid management can be a challenge in situations where multiple sources of hypotension may coincide.

The current recommendations in surviving sepsis guidelines recommend immediate infusion of  30 mL/kg of crystalloid in suspected sepsis with hypotension (about 2 Liters of fluid in the normal adult).  If hypotension continues, a vasopressor should be added. The general gestalt for most anesthesiologists treating a patient with a known perforation of the colon for emergency surgery would consider using rapid infusion of crystalloids as a mainstay for continued hypotension.  During my residency training, it was often stated and taught that giving vasopressors to a hypovolemic patient could results in vasoconstriction that leads to organ ischemia, and aggressive fluid (cyrstalloid) administration should continue during surgery.

However, more recently, clinicians are reconsidering and evolving the resuscitation methods during large and extensive surgery.  A large number of studies have looked at the detrimental effects of large amounts of crystalloids given to patients.  Another group of studies have specifically looked at restrictive volume strategies to improve outcomes in elective  bowel surgery patients.  Another group of studies have utilized a large number of methods to measure or estimate cardiac output to provide fluids in a goal directed manner to improve outcomes.  To date, there is still confusion as to what constitutes best practice.    What remains clear is that under resuscitated patients, or those who are hypovolemic for extended periods of time, suffer morbidity.  What has started to become equally clear, is that over hydration, can be equally detrimental.    

My patient had very little urine and what did appear was very concentrated.  Therefore, I pushed forward with a presumptive diagnosis of hypovolemia as at least one major cause of his ongoing hypotension.   I therefore began an aggressive fluid resuscitation with lactated ringers.   After four liters given over about 1.5 hours, there was little if any change in any of the patients parameters.  In fact, there was almost no urine output.  At this point I  gave 250 mL of 5% albumin.  Blood loss was not substantial, however, there was an approximate 3 liter loss of fluid from the peritoneal cavity of presumptive ascites.  It was noted that the patient had a visibly cirrhotic liver. Large volume paracentesis is known to lead to arteriolar vasodilation and an increase in cardiac output.  It is widely recognized that paracentesis induced circulatory dysfunction can lead to significant morbidity in patients with liver disease.  Management recommendations include post removal treatment with 125 mL of 5% albumin volume replacement per liter of ascitic fluid removed (if more than 5L is removed), and consideration of vasopressors such as terlipressin for continued hypotension.

Recently, a large number of studies have attempted to determine the best way to manage volume status in patients with or at risk for hypotension.  Maintaining perfusion pressure and thus DO2 to tissues is critical to avoid organ damage secondary to hypoxic injury.  However, some studies have also shown harm to patients associated with overhydration.  In Anesthesiology, a study [1] in radical cystectomy patients found that the rate of complications was 52% in a group of patients who received a low volume of LR vs a high volume of LR where the rate of complications was 73%.  The low volume group received LR at 1 mL/kg/hr until completion of cystectomy and then 3 mL/kg/hr until the end of surgery plus low dose norepinephrine.  The high volume group received  6 mL/kg/hr  plus 250 mL fluid boluses  as need during surgery.   Post op fluid therapy was similar between groups.  The rationale for using 6 mL/kg/hr in this study likely came from traditional teaching in textbooks such as Stoelting where we are taught that 6 to 8 mL/kg/hr should be used to maintain hydration in patients undergoing major abdominal surgery [2]. In 2003, Brandstrup et al was able to show a reduction in complications by using a low volume algorithm in elective colorectal surgery.  In that study, the high volume group received 7 mL/kg/hr x 1 hour, then 5 mL/kg/hr x 2 hours, and then 3 mL/kg/hr thereafter.  Blood loss was replaced by NS up to an EBL of 500 mL, and then colloid up to an EBL of 1500 mL. The restrictive group only received 500 mL D5W and 6% Hetastarch for blood loss up to 1500 mL.  The standard group received 5.4 L overall and the restrictive fluid group received only 2.7L.  Cardiopulmonary complications were reduced in the restrictive fluid group from 24% to 7% and the incidence of tissue healing complications was reduced from 31% to 16%.  In 2018 a large international RCT trial compared a restrictive fluid therapy regimen to a liberal strategy (RELIEF study) in patients having major abdominal surgery.  In the liberal group crystalloid was given at 10 ml/kg during induction of anesthesia, followed by an 8 ml/kg/hr infusion until the end of surgery.  Post op patients received 1.5 ml/kg/hr for 24 hours.  The restrictive regimen was designed to provide a net zero fluid balance. An infusion of crystalloid at a dose of 5 ml/kg/hr was administered until the end of surgery. Post op fluids were given at 0.8 ml/kg/hr.  During surgery, colloid or blood was given to replace blood loss in a 1:1 ratio.  The primary outcome measure was rate of disability free survival at 1 year.  There were no differences between groups for this outcome.  The secondary outcome was AKI which occurred in 8.6% of the restrictive group and 5% of the liberal group. The median fluid load given in the restrictive group was 1.7L for average surgery duration of 3.2 h while the fluid volume was 3L in the liberal group. It seems likely, that in this study at least, restrictive was too restrictive and the liberal group was more like the restrictive group of past studies. <0 .001="" 1.7l.="" 13.6="" 16.5="" 1="" 30-day="" 3="" 3l="" 40="" a="" abdominal="" about="" administered="" administration="" aki.="" an="" and="" anesthesiologists="" another="" appropriate="" as="" associated="" association="" average="" be="" between="" both="" but="" by="" can="" case.="" challenges="" characterized="" complications="" concluded="" consistently="" costs="" crystalloid="" defined="" difference="" differences="" during="" enough="" equates="" estimates.="" find="" fluid="" for="" found="" group="" hand="" have="" having="" he="" highest="" his="" hour="" in="" incidence="" intraoperatively="" l="" length="" less="" liberal="" lowest="" major="" moderate="" mortality="" n="" nbsp="" ndeed="" needle="" observational="" observed="" of="" on="" optimal="" other="" outcome.="" outcomes="" p="" patients="" postoperative="" quintile="" received="" regimen="" relief="" respiratory="" restrictive="" revealed="" same="" second="" secondary="" sick="" significantly="" small="" stay.="" strategy="" study="" surgery.="" surgery="" textbook="" than="" that="" the="" therapy="" there="" this="" threading="" to="" traditional="" trial="" u-shaped="" underscores="" volume="" volumes="" was="" we="" were="" whereas="" while="" with="">Traditional thresholds for intraoperative oliguria do not predict acute kidney injury (AKI).  In a  meta analysis [4] done in 2016 of 28 trials including both surgical and critically ill patients, less renal dysfunction was noted in patients receiving goal directed fluid therapy without the use of oliguria to guide fluid administration. Another meta analysis by Cochrane concluded, "The balance of current evidence does not support widespread implementation of this approach to reduce mortality but does suggest that complications and duration of hospital stay are reduced."  Specifically they showed that GDT reduced the rate of renal failure, respiratory failure and wound infection. Typically, goal directed therapy for fluid management has relied upon esophageal doppler technology to estimate stroke volume.  This technology is not readily available however.  Technology to analyze the arterial waveform to estimate pulse pressure variation (PPV) and stroke volume variation (SVV) as as well as systolic pressure variation (SPV) has been developed and is making inroads into many operating rooms.  However, these technologies are not wide spread and easily applied.  In 2012 Thiele et al published a study showing that anesthesia providers were able to make correct diagnostic decisions in 96% of situations using a simple visual "eyeball" review of systolic blood pressure waveforms attempting to estimate systolic blood pressure variation. This provides evidence that in patients who have an arterial line in place, anesthesiologists who do not have access to higher level arterial waveform analysis technology can be "good enough" in lower acuity situations to determine which patients need more fluid.

Goal directed therapy using stroke volume variation (SVV) or pulse pressure variation (PPV) and arterial waveform analysis has been studied intensely in the last decade.  The general concept relates to an attempt to determine if a patient who is hypotensive would respond to a fluid challenge (best is 3 to 4 mL/kg) by increasing stroke volume by about 10 to 15%.  During mechanical ventilation there is a rise in pleural pressure during the inspiratory phase which impedes blood return to the right atrium and thus the right ventricle. At the same time as right heart preload is decreased, right heart afterload is increasing during the inspiratory phase in conjunction with increased pleural pressure.  However, left ventricular preload increases while left ventricular afterload decreases. This transient alteration in right heart and left heart preload and afterload leads to a decrease in LV output a few heartbeats after completion of mechanical insufflation (or expiratory phase of mechanical ventilation). The changes in the RV and LV stroke volume with each mechanical breath are larger on the steep compared with the flat portion of the Frank Starling curve for four main reasons: 1) the SVC is more collapsible in hypovolemia, 2) the inspiratory increase in right atrial pressure is greater in hypovolemic states secondary to the greater transmission of pleural pressures to the more compliant right atrium, 3) the effect of mechanical inspiration on RV after load is greater because of higher trans alveolar pressures in the setting of hypovolemia, and 4) the ventricles are more sensitive to preload when they are operating on the steep portion of the frank starling curves.  To validate this Michard et al studied 40 patients with sepsis on mechanical ventilation.  This study found higher variations in pulse pressure (24% vs 7%) in a group of patients who responded to volume expansion (defined by a 15% increase in CI) vs those that did not.  They showed that if pulse pressure varied by more than 13% there was a 94% sensitivity (low false negative) and a 96% specificity (low false positive) in predicting volume responsiveness [5].  Nine years after this initial study, a meta analysis was completed by Marik et al [5]. This group looked at 29 clinical studies. They found that the area under the ROC curve was 0.94 for PPV and 0.86 for SVV. All other strategies utilized for determining volume status (CVP, global end-diastolic volume index, LVEDA index) performed poorly.  They also found a very consistent threshold for defining fluid responsiveness of 12 to 13%.   They also noted that there is a gray zone of 9 to 13% where fluid responsiveness cannot be predicted reliably and this 'gray zone' may affect up to 25% of patients during general anesthesia. Furthermore, in order to perform arterial waveform analysis using current technology, patients must be in sinus rhythm, be mechanically ventilated with tidal volumes greater than 7 mL/kg and not be receiving vasopressors.

When confronting a patient whose volume status is in question and hypotension is at hand, a detailed conceptual construct is helpful in understanding how to proceed.  This construct aids in understanding the mechanisms of how fluid therapy can be harmful or helpful and when. One concept that was previously highlighted in the journal Anesthesiology divides total blood volume into the stressed and unstressed volumes within the body. The 'unstressed' volume is that volume of blood that fills the blood vessels without causing a rise in pressure. The 'stressed' volume is any additional volume that results in a rise in pressure AND elastic distention of the vessel wall. Therefore, when a clinican administers a fluid challenge, they are aiming to expand the 'stressed' volume. Whether the fluid challenge leads to a rise in pressure or not is dependent upon whether it fills the 'unstressed' volume or the 'stressed' volume. This is dependent upon the overall venous compliance.  In 1894, Bayliss and Starling first described the concept of mean systemic filling pressure (Pmsf) in a dog model. This is defined as the pressure in the vascular system when the heart is stopped and there is no blood flow. Pmsf is a critical element in determining venous return along with right atrial pressure and resistance to venous return.  The driving pressure for venous return is the pressure gradient between Pmsf and central venous pressure (CVP) which then determines cardiac output.




It should be noted that with the induction of anesthesia, or other physiologic changes the unstressed volume can suddenly increase.  A sudden increase in the unstressed volume (see above figure) would then lead to a decrease in the Pmsf and thus reduce venous return and thus cardiac output. In a patient who undergoes a temporary state (i.e. general anesthesia) where the unstressed volume is suddenly increased due to sympathectomy, and this is filled aggressively with fluid, and then thereafter, the unstressed volume returns to its previous state (emergence), the patient could now be in a sudden state of fluid overload as the fluid placed into the unstressed volume is now recruited into the stressed volume per force. Therefore, the above conceptual framework allows clinicians to visualize the potential negative effects of overly aggressive fluid therapy. Conceptually, one might consider what happens to the Pmsf in a patient suffering a vasodilatory state such as sepsis.  In this scenario, once again, the unstressed volume is dramatically increased leading to a decrease in Pmsf which will decrease venous return and thus cardiac output.  If the treatment modality is only additional fluid to fill the unstressed volume, there is a real risk of too much fluid.  Therefore, the correct therapeutic modality  in treating an unnatural increase in the venous capacitance or unstressed volume are vasopressors. Vasopressors in this setting serve to return the unstressed volume back to its "natural" volume, at which time, additional fluid therapy can fill the "stressed" volume leading to an increase in Pmsf which would be clinically observable with an increase in SV or CO leading to improved blood pressure.

The above case represents a perfect example of a patient who had vasoplegia secondary to sepsis and therefore, a very large unstressed volume.  In addition, the patient was also likely suffering from a capillary leak syndrome leading to loss of intravascular fluid into the interstitium.  This fluid would need to be replaced.  However, the vasodilated state required Alpha 1 adrenergic therapy. There is evidence that early fluid therapy will do more than just increase the mean systemic filling pressure (Pmsf) promoting increased right heart filling pressures.  Early aggressive fluid therapy in sepsis can  also shift the cytokine response towards a more anti-inflammatory balance [8] and is associated with reduced mortality in septic patients [9].

In my patient after about 6 liters of crystalloid I infused 250 mL of human 5% albumin.  There is a great deal of controversy related to the type of fluids. Currently, there is no clear evidence that crystalloid (balanced salt solution) leads to greater mortality than colloid.  In addition hespan has fallen out of favor because it has been linked to AKI in critically ill adults.  Risk of HES-induced renal toxicity depends primarily on the molar substitution.  For example, the commonly available Hespan or hydroxylethyl starch 6% has a MW of 600 and degree of substitution of 0.75.  This formulation started to fall out of favor initially in 2003 when the FDA required that a new label be applied to 6% hetastarch (HESPAN) that recommended against HESPAN in bypass patients due to concerns related to coagulopathy. Newer HES solutions (tetrastarch 130/0.4) are considered far less toxic to the kidneys.  A recent [10] observational study compared a newer HES (130/0.4) to crystalloid and found that  HES was not associated with an increased frequency of post op kidney failure. Also, in-hospital mortality and ICU requirements were not different between groups. This was a mixed cohort of elective surgical patients. Another study comparing HES 130/0.4 to 5% albumin found no differences in renal function in a small RCT in patients undergoing cystectomy. Another study of HES 130/0.4 found that this formulation could reduce the inflammatory response in patients undergoing major surgery compared to a purely crystalloid based volume regimen. In larger meta analyses where a large number of different types of starches were compared to crystalloids, the incidence of RRT was greater in the patients receiving starches. In another study using pentastarch (200/0.5) vs LR there was a larger incident of AKI in the starch group.  However, on subgroup analysis it was found that patients suffering the negative renal outcome were given a larger than usual volume of pentastarch. Patients given less than 22 mL/kg of pentastarch actually suffered a significantly lower mortality (31% vs 58%) vs high dose penta starch and vs. LR (41% mortality). Furthermore, starches, especially those with a high degree of molar substitution (i.e. 0.75) are associated with a greater risk of bleeding and transfusions as per large meta analyses. Fortunately, once again, lower molar substitution products (tetra starch=0.4) seem to have a smaller effect on hemostasis. Avoiding these products (starches in general) would likely be important in particular in the above case as it was found that the patient had a fairly large amount of ascites upon opening the abdomen with a liver that appeared markedly cirrhotic. Although the patient had normal coagulation parameters prior to surgery with no evidence of decreased liver function, it is possible that the patient had some degree of platelet dysfunction from his liver disease which would be a relative contraindication to any form a starch fluid therapy.

In 2008, a lengthy review article was published on periopeartive fluid management in Anesthesiology [109;723-740].  In addition to being an excellent general review of the literature on perioperative fluid management, the author reviews the importance of the glycocalyx and it's part in forming the enodthelial surface layer (ESL) (see fig).


This layer is critical in avoiding platelet aggregation, leukocyte adhesion and increased endothelial permeability.  The ESL can be damaged by ischemia reperfusion, proteases, TNF-alpha, oxidized LDL lipoproteins, and atrial natriueretic peptide.  Therefore, two important things should be noted: 1) overly aggressive fluid hydration even in healthy volunteers may damage the ESL leading to pathologic fluid losses via damage to the ESL.  2) Major surgery and/or patients in a state of sepsis where a large inflammatory response is expected will also have a damaged ESL and pathologic shift of fluids into the interstitial space.  Quoting the article from Chappell in Anesthesiology, "Consequently, the primary indication of crystalloids is replacement of fluid losses via  (1) insensible perspiration and (2) urinary output. Colloids, by contrast, are indicated to replace plasma deficits due to (2) acute blood loss or (2) protein-rich fluid shifts toward the interstitial space (pathologic type 2 shift)."  Therefore, for major surgery, crystalloids would be indicated to replace insensible losses estimated to be about 1 mL/kg/hr (per chappell article).  All other fluid needs (i.e. from pathologic type 2 shift (shift of fluid across the endothelial glycocalyx into the interstitium) should be replaced by a colloid solution.  Unfortunately, HESPAN is no longer available and HES (130/0.4) is likely to be unavailable as well. 5% albumin is the only choice available in our hospital.  Given that the current evidence does not seem to indicate a clear and defined cut off for crystalloid where it is clear that you are killing patients, heavy use of crystalloid is still the mainstay given a lack of alternatives.

Therefore, in the above case, I might have selected a larger 5% albumin dose, maybe 1 liter, but ultimately, given the degree of the fluid needs, I would have been forced to use a fairly large volume of crystalloid.  Unfortunately, the vast majority of this crystalloid found its way into the interstitial space (chappell estimates it's actually 5:1 into the interstitial space not 3:1 as historically taught).  Patients with sepsis are also suffering from vasoplegia.  Therefore, using the above definition, there unstressed volume will be pathologically increased.  An IV vasopressor infusion to decrease the unstressed volume was also critical in facilitating the fluid resuscitation.

In summary, this case represents a patient with a perforation of the large bowel presenting with a significant systemic inflammatory response resulting in shock requiring emergent open abdominal surgery and aggressive fluid therapy.  In addition, the patient had co morbidities of liver disease, coronary artery disease, and insulin requiring diabetes.  Fluid management was reviewed and an understanding of the mechanisms of how to determine the volume status of patients using objective measures such as PPV to achieve a goal directed infusion of fluids was highlighted.  Furthermore, the pros and cons of crystalloid vs colloids was addressed highlighting that crystalloids should in general be reserved to treat ongoing insensible fluid losses while colloids should be utilized for all type II or pathologic fluid losses (including hemorrhage and fluid crossing the endothelial layer into the interstitial space.

1. Wuethrich P, Burkhard F, Thalmann G, Stueber F, Studer U. Anesthesiology. 2014 FEB
2. Stoelting et. al. Basics of Anesthesia, 5th ed. Elsevier – China, p. 349, 2007
3. Brandstrup B et. al. Ann Surg 238: 641, 2003
4. Egal M, Erler NS, de Geus HR, Van Bommel J, Groenevald AB. Anesth Analg. 2016; 122:173-185.
5. Michard F, Boussat S, Chemla D. et al. Am J Resp Grit Care Med. 2000; 162: 134-138.
6. Myles PM et al. NEJM. 2018; 378:2263-2274.
7.  Shin CH, Long DR, McLean D, et al. Ann Surg 2017 Mar 10
8. Dorresteijn MJ, van Eijk LT, Netea MG, et al. J Endotoxin Res. 2005;11:287–293.
9. Lee SJ, Ramar K, Park JG, et al.  Chest. 2014;146:908–915.
10. Pagel JI, Rehm M, Kammerer T, Hulde N, Speck E, Briegel J, Reinholz F, Crispin A, Hofmann-Kiefer KF. Anesth Analg. 2018; 126(6): 1949