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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 homocystenemia vascular disease in addition to inhibition of HDL biosynthesis in humans. 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 looked at [7] 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 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-adenosylmethioine (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 abuse N2O.  Patients present days up 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 can occur or permanent disability. 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, it shed light on concerns that acute elevation of homocysteine levels lead to increased cardiovascular events. 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 Analg. 2000;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.
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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 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 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 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 arterial waveforms 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" to determine which patients are fluid responsive.

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 to 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 interstitial.  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..
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A 34 year old female required cerclage for incompetent cervix and presented to the OR for the procedure.  I discussed the pros and cons of GA vs. regional neuraxial anesthesia and we proceeded with spinal anesthesia.  The patient was taken to the OR, 6.5mg + 20 mcg fentanyl was administered via 25 G whitakre needle.  The patient remained seated for aproximately 1 minute and then was layed supine.  The patient received no sedation via the intravenous route.  The patient tolerated the procedure without any problems.

The patient went to PACU able to move her legs but complaining of sinificant pruritis for which she reqeusted treatment.  She was discharged after a 2 hours and 37 min in the PACU after a case that was 30 min in duration.  

Management of the pregnant patient brings about a lot of questions for the anesthesiologist. Determining what anesthetics are safe and if needed what can be used to treat common side effects of anesthesia must be considered.  For example, in our patient, pruritis is typically treated with benadryl.  This medication may not be appropriate for the parturient however.  In general, I prefer to provide spinal anesthesia for cerclage. While there is currently no evidence to indicate that anesthetics are teratogenic, there is a growing literature demonstrating that anesthetics are neurotoxic to the fetus or early developing brain. While large human studies in pediatric patients seem to indicated that there is no significant increased risk to the brain, we have no good studies to indicated that there is not alteration to neurogenesis in the fetus.  Furthermore, even thought we do not have evidence of harmful fetal affects of anesthetics, we also lack good solid randomized controlled trials to prove an absence of negative effects.  If you perform an anesthetic on a patient who is pregnant who goes on to deliver a newborn with obvious defects, not otherwise explained, you carry potential legal risk unless you can establish that general anesthesia was truly your only option.  Juries do not evaluate the potential cause of harm to the fetus like you or I, and therefore, the legal risk is greater than you might expect.  

Giving spinal anesthesia to a patient who is to be discharged the same day creates panic in surgeons and facility administrators who are convinced that the patient will require prolonged care due to inability to void.  Therefore, in some case overcoming this concern can be prohibitive.  Avoiding prolonged PACU stays (due to post operative urinary retention [POUR]) is accomplished by modification of typical intrathecal doses.

The control of micturition is a complex process involving multiple afferent and efferent neural pathways, reflexes and central and peripheral neurotransmitters.  It is well known that bupivacaine and tetracaine delay return of bladder function beyond the resolution of sensory anesthesia, and may lead to distention of the bladder beyond its normal functioning capacity.  This may result in bladder damage. The normal bladder has a capacity of between 400 mL and 600 mL.  The detrusor muscle is innervated by efferent somatic, sympathetic and parasympathetic fibers.  The parasympathetic fibers cause contraction of the detrusor and relaxation of the spinchter, permitting micturition. The sympathetic fibers produce detrusor relaxation and internal urethral sphincter closure.  The two systems are governed by spinal reflexes and two pontine brain stem centers. General anesthesia casues bladder atony. Volatile anesthetics as well as sedative-hypnotics inhibit pontine the pontine micturition center and voluntary cortical control center of the bladder.  IT injection of bupivacaine will block afferent and efferent neural transmission from and to the spinal segments (S2-S4).   Typically, complete normalization of detrusor strength occurs 1 to 3.5 h after ambulation. IT injection of opioid decreases the urge sensation and detrusor contraction largely by opioid effect on opioid receptors in the spinal cord that decrease parasympathetic firing.  Theses effects as well as others, can be reversed with naloxone administration. It is understood that opioids added to IT local anesthetic increases the rate of POUR.   This concept was looked at in an article by Niazi et al. [1].  They compared three groups of patients who received hyperbaric bupivacaine 0.5% (15 mg) (S1), bupi 15 mg + fentanyl 20 mcg (S2) or GA (G).  The incidence of POUR was 20% in group S1, 35% in group S2, and 8% in group G.  There incidence of 35% of POUR in the local + fentanyl group was much higher than another study [2] where the group with fentanyl given IT had POUR of only 20%.  This is likely because in this study only 7.5 mg of bupicacaine was used and 25 mcg of fentanyl.  The impact of bupicavaine dose was considered in a study that compared bupivacaine with lidocaine for spinal anesthesia for cervical cerclage.  In this study, the bupivacaine dose was 5.25 mg with 20 mcg of fentanyl added.  This was compared to lidocaine 30 mg + fentanyl 20 mcg [3]. They did not detect any difference between the two anesthetics with regard to onset and recovery time. They concluded that low dose bupivacaine (5.25 mg) offered a similar recovery profile to lidocaine IT 30 mg.  They did have 2 of 30 women in the lidocaine group with complaints consistent with TNS that resolved in 48 hours.  Indeed, lidocaine is really the gold standard in regards to outpatient spinal anesthesia.  Due to its reputation of causeing TNS, it has fallen into disuse.  TNS or transient neurological symptoms is described as transient buttock pain, radicular lower extremity pain, and dysesthesias that present within the first 24 hours following recovery from spinal anesthesia.  Some have reported an incidence as high as 40% with lidocaine. There is also some who speculate that the hyperbaric lidocaine solution (5% hyperbaric could be the cause) of TNS.  A recent study of  50 patients using 2% isobaric lidocaine as a single IT dose did not find a single case of TNS [4].  Unfortunately, this paper did not disclose the lidocaine dose.  This is important, because some studies suggest that the incidence of TNS is dose dependent [6].  In fact, some research or analysis of research suggests that using a lidocaine dose of less than 25 mg might prevent TNS from lidocaine.  The above study failed to cite another study performed in 1998 (Anesthesiology [5]). In this publication isobaric lidocaine 60 mg at a 2% concentration was compared to mepivacaine 1.5 %.  They found a 22.2% incidence of TNS with this formulation of lidocaine vs 0% in the mepivacaine group.  Another group used 10 mg lidocaine for spinal anesthesia and found a 0% incidence of TNS [7] with good operating conditions for prostate bx.  Another group compared knee arthroscopy in patients who received IT unilateral  bupivacaine 3 mg + fentnayl 10 mcg vs bilateral lidocaine 20 mg + fentanyl 25 mcg [8].  In this study no patients in either group suffered TNS (each group had n=25).  The incidence of pruritis was 5/25 patients and 7/25 patients in the bupi group vs the lido group.  Urinary retention not requiring bladder catheterization was found in 2/25 patients in the bupivacaine group (however the p value was 0.149).  They reported 100% excellent operating conditions for knee arthroscopy, with a duration of sensory block of 157 min in the bupivacaine group and 129 min in the lidocaine group. Time spent in the PACU was 39 min vs 0 min in the bupivacaine vs lidocaine group, time to ambulate was 159 min vs 3.6 min and time to home readiness was 184 min vs 153 min in the bupivacaine vs lidocaine group respectively.  while this was a small study, it seems to emphasize that with 20 mg of lidocaine + fentnayl, you can achieve a very short PACU stay, nominal risk for urinary retention, with very low chance of TNS.  Unfortunately, in many institutions, spinal lidocaine is simply not available.  Therefore, low dose bupivacaine is an alternative.  I opted for 6 mg of bupivacaine, but as mentioned there is some evidence that 5.25 mg of bupivacaine is sufficient for cerclage.  

1.  Niazi AAA, Taha MAA. Egyptian Journal of Anesthesia. 2015. 31:65-9.

2. Gupta A, Axelsson K, Thorns, E, et al. Acta Anaesthesiol Scand 2003;47:13-9.

3. Beilin Y, Zahn J, Abramovitz S, Bernstein HH, Hossain S, Bodian C.  Anesth Analg. 2003; 97: 56-61.

4. Frisch NB, Darrith B, Hansen DC, Wells A, Sanders S, Berger RA. Arthroplast Today. 2018;4:236-39.

5. Liguori GA, Zayas VM, Chisholm MF. Anesthesiology 1998. 88; 619-23.

6. Buckenmaier CC III, Nielsen KC, Pietrobon R, et al. Anesth Analg 2002;95:1253-7.

7. Nishikawa K. et al. Jour of Clinical Anesthesia 2007;19:25-9.

8. Hassan HIEA, Anesth Essays Res 2015. 9:21-27.
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A 26 year old female with previous bowel surgery for superior mesenteric artery (SMA) syndrome, presents to have a revision of her gastrojejunal anastomossis.  SMA syndrome occurs when the aorta and superior mesenteric artery wrap around the duodenum in such a way as to compromise the passage of food through the narrowed part. The syndrome is often related to loss of the mesenteric fat pad in the area. In this case the patient suffered from anxiety and a history of anorexia nervosa likely leading to the loss of the mesenteric fat pad. During two previous abdominal surgeries the patient suffered complications of post operative pain unrelieved by post operative thoracic epidural analgesia and multimodal analgesia.  She was also persistently nauseous and struggled to tolerate food post op.  She had to return to the OR a second time due to the development of a stricture post op in her small intestine.  The second surgery also resulted in a similar challenge of pain control with severe nausea.  The patient is now scheduled for a third surgery, a revision gastrojejunal anastomosis and gastrojejunostomy.

Given that the patient is very likely to suffer as in her prior surgeries with significant pain, I have decided to consider an aggressive multimodal pain regimen for post op pain.  Currently, many surgeons are requesting transversus abdominal pain blocks (often with catheters) for post op pain control after abdominal surgery.  In many cases, it appears that this method of pain control is supplanting TEA as the primary regional technique for pain control after abdominal surgery.  Unfortunately, I have had less success with the TAP technique for open abdominal surgery in particular with upper (above the umbilicus) abdominal surgery.  It is well known that the transverses abdominal plane block (TAP) provides somatic analgesia to the skin and anterior abdominal wall. Unfortunately, pain sensation from the viscera and peritoneum are not blocked with this technique as it is with epidural analgesia (EA).  Recently a head to head trial comparing TAP vs EA was published [1].  The authors found that in lower abdominal surgery, TAP had similar pain control to EA patients for the first 16 hours.  After 16 hours up to 48 hours, the group with epidural analgesia had better pain control.  For incisions above the umbilicus, it is recommended that a subcostal technique be used.  However, for long incisions, it is often difficult to get enough spread of local anesthetic in the transversus abdominis plane to block all of the necessary nerves. Nevertheless, Rao et al. were able to show that after major abdominal surgery, TAP catheters were equal to EA in terms of pain scores, opioid requirements, and patient satisfaction [2]. In another study of open laparotomy patients (n=51)[3], Ganapathy et al. found that TAP catheters were essentially equivalent to EA during 72 hours in terms of pain control. However, in another study, TAP catheters were inferior to EA for pain control after major open abdominal surgery [4].  A small meta analysis of four studies was unable to find any significant differences in pain control or opioid use after abdominal surgery when comparing TAP catheters with EA [5].  However, there was a trend toward increased morphine use in the TAP catheter group.  All, in all, it would appear that  for abdominal surgery TAP catheters can be a reliable alternatively to EA when pain control is the only outcome of interest. However, multiple studies and a cochrane review have shown that for the important endpoint of reduction in post operative ileus, EA is helpful.  (see here for cochrane review). In this particular case, post operative ileus is a major concern.  The patient is currently on TPN, due to continued poor oral intake.  It will be imperative to maximize her chances of avoiding a prolonged post operative ileus.  Therefore,  EA would be an ideal choice.  However, this patient is likely to still have significant post operative pain as she did after her prior two abdominal surgeries despite having a functioning thoracic epidural.  There is evidence that in patients with difficult to treat pain, that ketamine can be helpful.  There is a large literature related to ketamine use in the perioperative period. In 2010, a Cochrane review found that sub-anesthetic ketamine reduced analgesic requirements and/or pain scores in 27 of 37 RCTs [10].  Currently, most guidelines suggest giving a bolus of 0.5 mg/kg at the beginning of the case plus an infusion of 0.25mg/kg/hr during surgery.   De Koch et al. found that intraoperative ketamine  ( 0.5 mg/kg bolus + 0.25 mg/kg/hr infusion) reduced morphine consumption in patients having abdominal surgery [6].  Importantly, this occurred even though all patients received aggressive EA.  Furthermore, they were able to show that secondary hyperalgesia was reduced in the ketamine group and that in this group, chronic post operative pain was significantly less at 6 months after surgery.  Himmeslseher et al. published a meta analysis on ketamine for post operative pain control.  They recommend ketamine to reduce post operative pain and provided the following recommendations:

Major surgery:  0.5 mg/kg bolus prior to incision and 0.5 mg/kg/hr infusion until end of surgery. then post op infusion of 0.12 mg/kg/hr x 24 hours in the post operative period.

Minor surgery: 0.25 mg/kg bolus prior to incision + 0.25 mg/kg/hr infusion until the end of surgery.

Dosages above are fairly aggressive, and it is clear that post operative hallucinations, vivid dreams and other cognitive affects are more frequent and more severe at higher doses.  Therefore, I tend to decrease the doses from those recommended above.

Multipmodal analgesia will be very important so I will given IV Tylenol during the surgery and then q 8 hours post op.

 Another option is an IV infusion of Magnesium.  Magnesium as an adjunct for pain control has been considered for decades.  A large number of clinical studies looking at the use of magnesium for post operative pain control have been published with mixed results.  A systematic review in 2007 that included 14 studies could not detect a beneficial effect of systemic magnesium administration on post operative pain control [8].  In 2013, another systematic review was undertaken and was able to demonstrate a beneficial effect of magnesium on pain control [9].  The largest improvement was the reduction in morphine consumption as noted in the figure below.  Most of the studies utilized a 30 mg/kg bolus or a 50 mg/kg bolus +/- an infusion of  between 8 mg/kg/hr to 15 mg/kg/hr intraoperatively or a few even post operatively.

Fig 1 post operative morphine consumption is reduced with magnesium.

Magnesium acts as an NMDA antagonist to reduce the perception and duration of pain.

Recently, more and more groups have started to take interest in the possibility of gabapentin reducing post operative pain and/or analgesic opioid requirements. In 2013, an article in Anesthesiology stated that the current evidence suggested that gabapentinoids (gabapentin and pregabalin) could reduce preoperative acute pain/analgesic requirements and the incidence of post surgical chronic pain development.
gabapentinoid pharmacology: these are not active at the GABA-a receptor although they are GABA structural analgues.
These GABA analogues actually bind to the alpha 2-delta subunit of pre synaptic P and Q type voltage gated calcium channels.  Doesn't make much sense, but that's how they cause the effect we are looking for. This is believed to modulate the release of excitatory neurotransmitter from activated nociceptors. So, by inhibiting Calcium induced release of glutamine, these agents can inhibit pain transmission and/or decrease central sensitization.  Alternatively, some evidence indicates that their antinociceptive mechanism may arise through activation of noradrenergic pain-inhibiting pathways in the spinal cord and brain. (see figure)

In 2016 a meta analysis of gabapentinoids [11] in dosages from 300 mg to 1200 mg found that they were helpful in reducing morphine consumption for the first 24 hours after surgery.  They did report increased sedation levels in patients who received gabapentinoids, and there was no decrease in side effects such as pruritus, nausea or vomiting.  Two different studies looked at gabapentin as a part of a multimodal analgesia program and both concluded that it was of questionable benefit in this context. The first of these two studies was a RCT in TKA with gabapentin [12].  In this study patients were given 600 mg gabapentin preop with 200 mg q8 hours post op along with morphine, ketorolac and tylenol.   Morphine consumption and VAS scores were similar between groups.  Monks et al. [13] looked at gabapentin in post cesarean section patients at dose of 600 mg preop and 200 mg q8 hours post op. Patients received spinal morphine. There was a very slight decrease in morphine consumption in the group receiving gabapentin and the authors concluded that gabapentin is of questionable benefit in cesarean section patients.  One consideration that is important is to understand that gabapentin is an oral medication and was not possible to use in our case in a patient requiring TPN due to an inability to tolerate oral intake.  In addition, I was planning an aggressive multimodal pain program to include regional anesthesia, toradol, tylenol IV, magnesium infusion and a ketamine infusion, thereby making gabapentin an unlikely success in further reducing post op pain scores or opioid consumption.
One day prior to the scheduled surgery the pre admissions testing nurse called me to report that the patient had a lab drawn and that her potassium was 2.9 mEq/L. The nurse at the PAT clinic reported that the patient had a PICC line where she receives TPN in addition to potassium replacement.  The nurse also revealed that the patient suffers from orthostatic hypotension for which she is prescribed midorine and fludrocortisone.  I instructed the nurse to call the patient and have her stop her fludrocortisone the day before surgery and to come in early for repeat K+ lab draw with an order to start 20 mEq of postassium if her K+ level was below 3.1 mEq/L.

Orthostatic hypotension is often caused by failure of the autonomic nervous system. There are a variety of reasons for failure of the autonomic nervous system including:
  • Multiple system atrophy
  • familial dysautonomia
  • dementia with lewy bodies
  • Shy-Drager's syndrome
  • Parkinson's disease
  • longstanding diabetes
  • Vitamin deficiencies (our patient)
  • Amyloidosis
  • Bronchogenic carcinoma
  • Pure autonomic failure
Treatment for othorstatic hypotension can include a direct vasocontrictor.  My patient was taking midodrine, which is a prodrug and acts on the alpha 1 adrenergic receptor to cause vasoconstriction. Unfortunutely, this can lead to supine hypertension that is severe in some patients. This supine hypertension can result in pressure natriuresis leading to a worsening of orthostatic hypotension.  In patients taking midodrine for autonomic failure, there is typically an associated denervation hypersensitivity making these patients exquisitely sensitive to norepinephrine.   Patients with autonomic failure have other clinical manifestations as well.  These may include post prandial hypotension, urinary bladder dysfunction leading to urinary retention, and decreased gastrointestinal motility.

Fludrocortison is a mineralocorticoid used in patients with orthostatic hypotension.  It results in fluid retention and patients often will gain 2 to 3 Kg of water weight before receiving full benefit of this medication. Fludrocortisone does have some  glucocorticoid activity above dosages of 0.3 mg per day and this must be considered as to whether the HPA axis may be inhibited.  Mineralocorticoids act by mimicking aldosterone (binding to the aldosterone receptor in the cell necleus) which causes sodium retention at the expense of excretion of potassium and hydrogen ions. The action occurs in the renal collecting tubules.   This can lead to severe hypokalemia and metabolic alkalosis.  In addition, about 10% of patients also suffer from hypomagnesemia with chronic fludrocortisone therapy.  Because fludrocortisone does have some glucocorticoid activity, I could not ensure that the patient's HPA axis was not suppressed, and therefore, in addition to 4 mg of dexamethosone (purely glucocorticoid activity) I gave a one time dose of solucortef 50 mg.  This medication has both glucocorticoid and mineralocorticoid activity. 

On the day of surgery the patient arrived and a repeat potassium level came back at 3.3 mEq/L. Therefore, KCL infusion was not required prior to proceeding as I was worried might happen.  As discussed above, there is evidence that EA and bilateral subcostal TAP catheters are equivalent.  It was decided to proceed with GETA and post operative placement of subcostal TAP catheters.  The patient weight was 50 kg.  The patient was given 2 mg of versed and 2 mg of dilaudid and we rolled to the OR.  Induction was with propofol and rococuronium.  The patient was given ketamine in 25 mg increments to a total of 100 mg.  She was given MgSO4 2 GM intraoperatively, and another 1 GM was infused post operatively.  She also received decadron 4 mg, solocortef (to add some mineralocorticoid activity) 50 mg, IV tyelonol 1000mg, and zofran 4 mg.  The open laparotomy with revision of gastrojejunal anastomosis was uneventful and the patient arrived in the PACU extubated and breathing comfortably.  After 30 min the patient was interviewed and complained of 8/10 pain.  The nurse administered opioid pain medications.  A post operative ketamine infusion was begun at 5 mg/hr with a magnesium infusion of 250 mg/hr.  She received an additional amount of magnesium in her TPN solution.  The surgeon also prescribed a PCA with hydromorphone.  On POD 1, the patient appeared comfortable in her bed but complained of 8/10 pain.  It should be noted that on the first night on the day of surgery, the nurses called me to tell me that the patient had respiratory depression and that they had d/c'd all of her pain medications until she woke up.  It was decided to restart her magnesium and ketamine infusion, and cut her hydromorphone dose in half.  The patient requested EA, however, the surgeon intervened to avoid this.  The patients was NPO and therefore, not receiving fludrocortisone or midodrine, both oral medications.  Her blood pressures were low normal.

In this case, EA is likely to have been a better choice than TAP catheters.  Particularly on POD 1 when it became apparent that the patient had an event of respiratory depression from opioids requiring adjustment of the medication.  In addition, the patient perceived that her pain control was not adequate nor being addressed.  She stated that the TAP catheters were not working.  A test with ice to the skin around the incision was unable to detect any decrease in sensation or perception of cold.  This is a fairly good indicator of failure of block.  I have a long experience with the placement of TAP catheters and doing the subcostal block.  This patient was thin, and the US guided block went flawless, with excellent landmarks that were well visualized. However, the subcostal approach relies on local anesthetic spreading throughout the transversus abdominis plane and finding the nerves as they run along to their destination.  The actual nerves are not visualized and it is impossible to guarantee that all of the nerves will be bathed in local anesthetic (LA).  This is also true for EA, however.  The patient did state that the block was patchy.  To me this indicated that indeed the LA was located around several nerves, but that there were others not reached by the LA. This, to me constitutes a general weakness of the TAP approach than my technique.  On POD 2 the patient appeared much more comfortable and in fact had reduced the amount of opioid pain medication she was consuming.

1. Sadasivan Shankar Iyer, Harshit Bavishi, Chadalavada Venkataram Mohan, and  Navdeep Kaur,  Anesth Essays Res. 2017 (11)7: 670-675

2. Rao Kadam V, Van Wijk RM, Moran JI, Miller D. Anaesth Intensive Care. 2013;41:476–81.

3. Ganapathy S, Sondekoppam RV, Terlecki M, et al. . Eur J Anaesthesiol 2015;32:797–804

4. Wahba SS, Kamal SM. . J Anesth 2014;28:517–23.

5. Zhang P, Deng XQ, Zhang R, Zhu T.  Br J Anaesth. 2015;114:339. 

6.  De Kock M, Lavand'homme P, Waterloos H.  Pain 92(2001) 373-380.

7. Himmeslseher S, durieux ME. Ketamine for perioperative Pain Management. Anesthesiology. 2005; (102):211-20.

8.  Lysakowski, C, Dumont, L, Czarnetzki, C, Tramèr, MR . Anesth Analg. (2007). 104 1532–9 

9. Gildasio S. De Oliveira, Jr, M.D., M.S.C.I.; Lucas J. Castro-Alves, M.D.; Jamil H. Khan, B.S.; Robert J. McCarthy, Pharm.D. Anesthesiology 07 2013, Vol.119, 178-190

10. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006

11. Sudha Arumugam, Christine SM Lau, and  Ronald S Chamberlain. J Pain Res. 2016; 9: 631–640.

12. Paul JE, Nantha-Aree M, Buckley N, Cheng J, Thabane L, Tidy A, DeBeer J, Winemaker M, Wismer D, Punthake D, Avram V; Gabapentin does not improve multimodal analgesia outcomes for total knee arthroplasty: a randomized controlled trial; Canadian Journal of Anesthesia 2013, 60:423-431

13. Monks DT, Hoppe DW, Downey K, Shah V, Bernstein P, Carvalho JCA; A perioperative dose of gabapentin does not produce a clinically meaningful improvement is analgesia after cesarean delivery; Anesthesiology 2015 August, 123(2): 320-326
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Recently my partner placed an interscalene brachial plexus block with catheter in a patient who had a BMI of greater than 60.  The patient was at risk for post operative respiratory insufficiency due to the known complication of phrenic nerve palsy on the ipsilateral side of the block, which results in an elevated diaphragm on chest x ray. (see figure 1).
fig 1
Patients having arthroscopic shoulder surgery are most commonly scheduled for day surgery, and admission to the hospital for hypoxia associated phrenic nerve paralysis is suboptimal.  Patients with intrinsic lung disease are at risk for this complication.  Patients who are morbidly obese are also at risk for this complication [1].   Unfortunately, it is not always easy to tell ahead of the block who will develop clinically relevant complications as a result of phrenic nerve palsy after interscalene block.  A large retrospective review was published on cases of outpatient interscalene catheter usage (n=509) [12].  Adverse events were recorded in 6.7% of patients.  Of these only 0.6% (3 patients) had problems or complaints of dyspnea all of which were after discharge to home. However, the mean BMI was 24, with no patient having a BMI greater than 29.  In addition, all patients with any lung disease were not included in the study.  

At the level of the interscalene block, the phrenic nerve lies in close association with the brachial plexus cords/trunks. (see fig 2). Its course is most proximate to the brachial plexus at the level of the interscalene block where it typically is 18 to 20 mm away from the C5 nerve root at the level of cricoid cartilage.  
fig 2
However, as one moves caudad, the phrenic nerve moves an additional 3 mm further away from the plexus for every cm that it descends over the anterior scalene muscle.  
A review article on the options for avoidance of significant phrenic nerve block was published in the journal Anesthesiology in 2017 [2].  This article is highly recommended for the practioner who desires a more in depth understanding of brachial plexus and phrenic nerve anatomy.

Patients who are obese are more likely to experience dyspnea in association with phrenic nerve palsy. Furthermore, it is likely that morbid obesity will also increase the risk of hypoxemia in association with dyspnea. There are several strategies to reduce the chances of this outcome and will be reviewed briefly. Traditional training of the ISB has recommeneded high volumes (30 to 40 mLs) to ensure complete blockaded of the brachial plexus. Reducing this amount could reduce the incidence of phrenic nerve palsy. However, most studies indicated that volumes of 20 mL or greater will inevitably result in phrenic nerve palsy if the injection occurs around the C5-C6 nerve roots. US guided techniques have allowed practitioners to be more precise in the placement of the local anesthetic permitting a lower volume to achieve shoulder analgesia after interscalene block.  In particular, one study found that after 10 mL was injected, the chance of phrenic nerve palsy could be reduced from 100% to 60% [3]. Reducing the injected volume to 5 mL can lower the chance of phrenic nerve palsy to as low as 27% [4] without compromising the block effectiveness for up to 24H.  However, it is well known that introducing a greater volume tends to increase the chances for success, and therefore, using 5 mL as a routine is likely to lead to suboptimal outcomes in some cases. Furthermore, given the problems with admitting a patient from an outpatient facility to a hospital secondary to respiratory compromise, an incidence of phrenic nerve palsy of 27% may seem high.  Nevertheless, further improvements seem possible if the concentration is reduced. To provide dense surgical anesthesia and prolonged dense post operative analgesia, I typically opt for 0.5% bupivacaine or Ropivacaine.  By halving the concentration to 0.25%, AL-Kaisy et al was able to reduce the incidence of phrenic nerve palsy from 100% to 17% [4].  However, this study only had 5 volunteers in each group. In a slightly larger group of patients (30), Thackeray et al.[5] were able to reduce the incidence of phrenic nerve palsy from 78% to 21% by halving the bupivacaine concentration with a 20 mL injection.  This reduciton in  concentration seemed to come at the expense of more opioid requirements over a 72 hours time frame and also a shorter block duration (18 hr vs. 11.9 hr) [6]. To add confusion to the previous studies, Zhai et al. couldn't find a significant differenence in phrenic nerve palsy when using a fixed dose of 50 mg of Ropivacaine for US guided interscalene block using concentrations of 0.25, 0.5 or 0.75% [7].
Perhaps more effective, is an injection of local anesthetic around the C7 nerve root.  When using 5 mL of a 0.75% concentration of Ropivacaine, no patients (n=20) had any diaphragmatic paresis after 2 hours post injection [8].  The calculated ED 95 was 3.6 mL of 0.75% ropivacaine for this study when injected around the C7 nerve root.
Performing a supraclavicular block as been studied as a method of reducing phrenic nerve palsy.  More specifically, targeting the superior trunk of the brachial plexus (formed by the union of the C5/C6 nerve roots), has been reported in two case reports to provide analgesia after shoulder surgery without blocking the phrenic nerve. At this level the phrenic nerve has migrated away from the brachial plexus.  An approach to target the superior trunk is to do a supraclavicular brachial plexus block. Mulltiple studies have looked at the supraclavicular block and the results are somewhat equivocal. For example, with injection volumes of 20 to 30 mL, phrenic nerve palsy occured in 25 to 51% of patients.  Furthermore, in some of the studies, patients receiving a supraclavicular block had inferior post op analgesia. On the other hand, Kim et al. were able to show that a supraclavicular block  performed equally to ISB for patients having shoulder surgery without GA in terms of conversion to GA (0 patients) or fentanyl requirements [14]. Given the above data, I have begun to modify my block for shoulder surgery, seeking to do what I consider to be a high supraclavicular block or perhaps a low ISB. I further modify my block in patients who I consider to be at higher risk for phrenic nerve palsy by reducing the volume of local anesthetic and perhaps also decreasing the concentration. 
    The above techniques may reduce the incidence of phrenic nerve palsy, but don't seem to eliminate the risk altogether. The risk of phrenic nerve palsy may be completely eliminated by avoiding any injection around the brachial plexus.   In 2012, Siegenthaler et al. desribed a novel approach to the suprascapular nerve [9].  In their study, a comparison study was done between locating the suprascapular nerve in the supraclavicular space vs. in the suprasspinous fossa.  They determined that  suprascapular nerve identification was much better in the supraclavicular space (81% identified vs. 36%). In my own practice, attempts at identification of the correct space using the supraspinous fossa (also known as the suprascapular notch) proved very difficult due to the greater amount of thick tissue overlying the area.  Furthermore, This approach requires a cooperative patient who can sit upright in order for the approach.  Lastly, I found that due to the depth of the area to be blocked, an acute angle was required making visualization of the needle problematic for accurate injection.  
The suprascapular nerve provides aproximately 70% of the innervation to the glenohumeral joint.  The majority of the remaining 30% derives from the axillary nerve.  Two recent studies published in Anesthesiology have looked at the effectiveness of suprascapular nerve block vs. interscalene block to determine non inferiority.  One was a meta analysis comparing the two approaches [10].  The meta analysis determined that a suprascapular nerve block alone was not inferior to an ISB.  In this meta analysis, only one study utilized a supraclavicular block in the supraclavicular fossa (all other studies approached the nerve from supraspinous fossa). The primary outcome for which the blocks were compared and found to be similar were for post operative morphine consumption (24H) and the cumulative difference between ISB and SSNB in the area under the curve for rest pain during the first 24H interval. This meta analysis did note, however, that during a 1 hour interval in the PACU, ISB provided superior pain control.  At 6,12,24, and 48hr there was no statistical difference. In this same meta analysis, it was found that ISB was associated with more respiratory complications, undesirable blockades, and block-related complications. 
    This month (july 2018), a head to head to head trial was published comparing analgesic efficacy between the anterior suprascapular, supraclavicular and interscalene nerve blocks [11]. The primary outcome was pain scores in the PACU.  The pain scores were 1.9,2.0 and 2.3 for the ISB, anterior suprascapular, and supraclavicular blocks respectively. The authors concluded that the anterior suprascapular nerve block was non inferior to the ISB. They also concluded that the supraclavicular block did not meet their prespecified criteria for non inferiority. They also found a significant decrease in respiratory function (measuring VC) for the ISB. (see fig 3).

In general, ISB is the gold standard for providing effective and consistent post op analgesia for shoulder surgery.  However, in day surgery patients who are likely to become hypoxemic (sat less than 90%) on room air after phrenic nerve block, the ISB is a relative contraindication.  Current research indicates that the only method found to virtually provide a 0% incidence of phrenic nerve palsy is a suprascapular nerve block.  Fortunately, several studies indicate that this block is likely non inferior to ISB in providing ample pain control.

Technique-Anterior Surpascapular nerve block:

place US probe in standard location as you would for ISB. Move the probe in a caudad direction as you follow the brachial plexus. (see figures below).

After determining the location of isolated SCN, only 3 to 4 mL are required to block this nerve at this level. Furthermore, due to the location of the nerve, a catheter could easily be inserted and secured in this location.
1. Hartrick CT et al. BMC Anesthesiol 2012;12:6.
2.  Deborah Culley Anesthesiology 2017;127:173-91.
3. Lee, JH, Cho, SH, Kim, SH, Chae, WS, Jin, HC, Lee, JS, Kim, YI R Can J Anaesth 2011; 58:1001–6
Stundner, O, Meissnitzer, M, Brummett, CM, Moser, S, Forstner, R, Koköfer, A, Danninger, T, Gerner, P, Kirchmair, L, Fritsch, G  Br J Anaesth 2016; 116:405–12
4. Al-Kaisy, AA, Chan, VW, Perlas, Br J Anaesth 1999; 82:217–20
5. Thackeray, EM, Swenson, JD, Gertsch, MC, Phillips, KM, Steele, JW, Burks, RT, Tashjian, RZ, Greis, PE  J Shoulder Elbow Surg2013; 22:381–6
6.Wong, AK, Keeney, LG, Chen, L, Williams, R, Liu, J, Elkassabany, NM Pain Med 2016; 17:2397–403
7.Zhai, W, Wang, X, Rong, Y, Li, M, Wang, H BMC Anesthesiol 2016; 16: 1–8
8. Renes, SH, van Geffen, GJ, Rettig, HC, Gielen, MJ, Scheffer, GJ  Reg Anesth Pain Med 2010; 35:529–34 
9.  Siegenthaler, A, Moriggl, B, Mlekusch, S, Schliessbach, J, Haug, M, Curatolo, M, Eichenberger, U Reg Anesth Pain Med 2012; 37:325–8 
10. Hussain N, Goldar G, Ragina N, Banfield L, Laffey J and Abdallah F. Anesthesiology 2017;127:998-1013.
11. Auyong DB, Hanson NA, Joseph RS, Schmidt BE, Slee AE, and Yuan SC. Anesthesiology 2018;129:47-57.
12. Marhofer P, Anderl W, Heuberer P, Fritz M, Kimberger O, Marhofer D, Klug W, and Blast J. Anaesthesia 2015, 70, 41-46.
13.Urmey WF, Talts KH, Sharrock NE Anesth Analg. 1991 Apr; 72(4):498-503.
14.Ryu, T, Kil, BT, Kim, JH  Medicine (Baltimore) 2015; 94:e1726
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