Case Reports in Anesthesia

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

March 16, 2020

Patient requesting labor epidural and a history of Idiopathic Intracranial Hypertension

This morning while watching the news showing the DOW plunging by another 2000 + points in the midst of a panicked public related to the spread of the novel corona virus, I was called up to L and D to place an epidural.  The patient was a G3P2 31 year old patient who was otherwise healthy with the exception of a reported prior history of Idiopathic Intracranial Hypertension.  She reported that she had been told that she could have an epidural by an anesthesiologist, but not a spinal.  Upon further questioning, I was able to determine that the patient had been treated by doxycycline for a routine URI or sinus infection.  Thereafter, she developed changes in her ability to see and sought medical care.  She was diagnosed with a reaction to the doxycycline and underwent lumbar puncture as part of the work up and therapy.  She states that after the lumbar puncture, she developed a headache which she had not suffered prior.  She was started on diamox and this was discontinued after a period of time.

At first glance, this seemed to be a case of primary idiopathic intracranial hypertension, when in fact, it was likely a case of secondary intracranial hypertension, meaning, caused by an external known cause rather than from a completely unknown cause.  Idiopathic intracranial hypertension is a diagnosis of exclusion. It typically affects females who are middle aged and obese. Upon LP, opening pressures of greater than 25 cm of H20 would be considered typical (normal opening pressure is 10 to 15 cm of H2O).  Patients with IIH can develop partial or complete blindness of one or both eyes if not treated.  In severe cases, when therapeutic LP or medicine like diamox or corticosteroids  are not working, surgical placement of an LP shunt is required.

For the OB anesthesiologist, any patient with potential intracranial pathology should be approached with caution.  Prior to any neuraxial procedure, it is important to fully understand the cause and natural history of any intracranial abnormality due to the potential catastrophic risk of brain tissue herniation.  An excellent review of the approach to the OB patient with intracranial pathology can be found here. In summary, patients who have obstruction to flow of CSF from the brain into the spinal canal are at high risk for any type of puncture of the dura mater. In the normal scenario when a puncture occurs of the dura mater in the lumbar portion of the spine, CSF will flow out and to compensate, CSF from the brain fills the space to equalize pressure throughout the continuous space. Any obstruction to this flow from from the cerebral ventricular system into the spinal canal will result in herniation.

However, patients with idiopathic intracranial hypertension (IIH) do not have a problem of obstruction of flow, and thus are not at risk for herniation after a dural puncture whether with a large bore or small bore needle.  As mentioned, LP is a therapeutic modality used to relieve headaches in these patients.  In patients with significant symptomatic IIH who wish neuraxial anesthesia for labor, there is a risk for potential exacerbation of symptoms (to include: pupillary changes or asymmetry, eye movement abnormalities, papilledema, hemiparesis, facial weakness, somnolence).   This is due to displacement of CSF from the lumbar spinal canal back up into the cerebral area. Furthermore, pregnancy and labor have been found to increase the baseline lumbar epidural pressure which it is thought is caused by engorged epidural veins. In studies of patients with elevated ICP, a 10 mL bolus of LA given over 20 to 30 s caused an average increase of 21 mmHg in ICP lasting 4.5 min vs an average increase of 6 mmHg for 2.3 min in a patient with normal pre injection ICP.  Therefore, this possibility should be discussed, and it may be a potential indication for a CSE, where a small IT dose can be given, and then a low volume infusion with PCEA can be offered to the patient to create a slow transition into epidural analgesia via lumbar epidural catheter. Indeed there are numerous case reports of successful neuraxial anesthesia for patients with IIH for both labor epidurals and cesarean sections. In this case report, the practictioner used the tuohy needle to drain 25 mLs of CSF prior to placement of an intrathecal catheter for labor analgesia. It was noted that the patient had excellent analgesia for labor and delivery, and did not suffer a PDPH, although the patient did complain of a headache.  Indications for an IT catheter might include patients where avoidance of GETA is important and likelihood of cesarian is also high.  The authors of the case report felt that their patient fell into this category.  They also noted that in a patient with difficult to control increased intracranial pressure, bolus doses through an epidural catheter may not be tolerated.

It is known that tetracycline, doxycycline and minocycline can all result in elevated intracranial hypertension.  Therefore, anytime a patient is treated with these antibiotics, any headache should prompt careful evaluation for this diagnosis. Currently it is unknown how these antibiotics can result in this disorder, although there is speculation that the antibiotics interfere with the production of ATP at the site of CSF absorption into the venous sinuses known as the arachnoid granulations.

My patient had been treated with Diamox or Acetazolamide, which is a carbonic anhydrase inhibitor. It is often noted that this action is predominantly effective at the renal tubule to reduce hydrogen ion secretion and increase the excretion of sodium, potassium, bicarbonate, and water.   Other uses include the treatment of glaucoma, seizures, and metabolic alkalosis due to its ability to dump bicarb and retain hydrogen ions. Diamox also inhibits carbonic anhydrase in the brain, and specifically in the choroid plexus, the site of CSF production, causing a decrease. Unfortunately, patients with IIH who are controlled with diamox will often be told to discontinue the medication while they are pregnant due to some case reports of congenital abnormalities and literature in animal models showing potential teratogenicity.  However, a recent study found no evidence for harmful effects of diamox in human pregnancy. Therefore, when a patient arrives for delivery, it is possible that she is still taking diamox to control her symptoms. If this is the case, it will be important to consider the effects of diamox on a potential anesthetic, primarily the risk of hypokalemia.

Patients who arrive for labor are always at risk for the potential to require anesthesia for cesarian section.  While neuraxial anesthesia is the preferred method overall, GETA may be required for a number of reasons.  In this case, there is a question as to whether succinylcholine should be used as it may cause a minor increase in ICP.  Furthermore, careful consideration of PaCO2 managment will be important as any increase in ICP will accompany hypercarbia. Definitive measures used for decreasing the ICP include, mild head elevation, maintain EtCO2 between 25 mmHg and 30 mmHg, I.V. mannitol, continuous infusion of propofol, avoid hypoxia, hypercarbia, hyperthermia and hypotension.

Anesthesia OB management for patients with IIH is generally straightforward, but careful history and a detailed understanding of the patients history and manifestation are important to avoid confusion with other intracerebral pathology that may also present during the peripartum period, such as PDPH and venous sinus thrombosis that can make diagnosis more challenging.  

February 23, 2020

Severe toxic Megacolon secondary to Ischemic Colitis

A  76 Year old male was admitted to the hospital after a syncopal episode during a BM at home.  The patient was found to be constipated and admitted for further testing. The patient deteriorated in a day and a half and required intubation due to ventalitaory failure. Pressors were required in low dose shortly thereafter, with accompanying renal failure.  The GI physician was called in on Sunday morning to attempt colonic decompression via a colonoscopy and I was called into the hospital to provide anesthesia.  I explained to the GI doctor, that giving additional sedation to the patient might cause additional decompensation.  Therefore, I ordered the ICU nurse to given 30 mg of Rocuronium, so the GI doc could proceed without any movement from the patient. This was done about 8:30am without problems. However, the patient continued to deteriorate requiring max dose of Norepinephrine (30mcg/min) and vasopressin at 0.02u/min.  Patient was taken emergently to the OR at about 4:30pm sunday afternoon for ex lap and total colectomy with ileostomy.

Upon transport to the OR, the patient was receiving the above mentioned infusions, plus insulin 4 u/hr, diltiazem for new onset AF, Bicarbonate drip, and precedex at 0.2 mcg/kg/hr.  These were all continued during surgery with the exception of the diltiazem.

 Upon arrival to the OR I placed a left radial arterial catheter for invasive pressure monitoring.  US was used and visualizing of the artery revealed a virtually pulseless distal artery despite NIBP blood pressures reading 100/50 mmHg.  After cannulation, there was almost no pulistile flow from the catheter causing me to question whether I had cannulated the artery or a vein. After connection to the transducer, an obviously arterial tracing was visualized on the monitor.  However, there was a very wide discrepancy between the NIBP  reading and the AL reading.  In general, the NIBP of the same arm was 45 mmHg higher for systolic pressures. All attempts to reduce this discrepancy failed.  The waveform was not dampened, there was excellent blood flow when withdrawing from the AL, the transducer was carefully zeroed twice, and placed at a similar level as the NIBP cuff.  The cuff was on the same arm as the AL.  Therefore, throughout the case, the AL was used mostly for trending, while I chose to accept the NIBP reading as more indicative of the actual pressure experienced by the patient.

Here are some serial ABGs
The patients labs were as follows: (day of surgery was 2/16).
ABGs (serial)
2/15--7.3 19:00 (lactate 7.2)
Na+: 138 mEq/L
K+: 4.2 mEq/L
Cl-: 99 mEq/L
CO2: 21
BUN: 54 mg/dL
Cr: 4.3 mg/dL

The patient was on  a bicarb infusion and I continued this to the OR.  I admit that I found this unusual and wondered what the evidence was to support treating severe lactic acidosis  from severe ischemic colitis with bicarbonate therapy.  In general multiple studies in critically ill patients with metabolic acidosis have not found any benefit to bicarbonate therapy for improving outcomes.  However, in one small study, patients with lactic acidosis AND AKI did have improved mortality when treated with bicarb [1].  In studies on patients in code situations, bicarb therapy has not improved outcome and is likely contraindicated.  Bicarb is most definitely indicated for patients with RTA I, or proximal RTA where bicarbonate is wasted, or not efficiently reabsorbed by the kidneys. However, RTA I leads to a chronic metabolic acidosis and is not relevant to our patients condition.  To me, it is not clear that our patient met the criteria of the patients in the study that found a benefit of bicarb therapy.  Prior to surgery the patient was anuric and had near complete renal failure, as opposed to AKI.  In the above mentioned study, it should be noted that the authors found that in patients who did not have AKI and were treated with sodium bicarb, there was an increase in mortality after correction for disease severity. The authors noted that this may be related to the fact that severe acidosis inhibits the enzyme phosphofructokinase which is responsible for the production of lactate.  By increasing pH, this enzyme is unleashed to continue to produce additional lactate worsening the acidemia unless the underlying cause of the production of lactate is corrected.  It is of note, that in the cited above study, patients treated with sodium bicarb did not see a reduction of blood lactate levels to the degree of those patients with a similar acidemia who did not receive sodium bicarb therapy. It should be noted that in non mechanically ventilated patients, sodium bicarb therapy for metabolic acidosis can be particularly detrimental since this therapy rapidly increases gaseous CO2 in the blood. As PaCO2 increases, a respiratory acidosis may ensue, and as CO2 rapidly enters cells, intracellular acidosis may become significant evens as blood HCO3- decrease.

It is noteworthy, that prior to surgery, my patient's lactate was 7.2 mg/dL, after surgery it had jumped to 12.2 mg/dL.  Lactate clearance has been shown to be  much better predictor of mortality than other  predictors [2]. In the ARISE trial, septic patients with high lactate levels had higher mortality than those who presented with hypotension only [6].  This massive increase also lends weight to the evidence described above that bicarb therapy may worsen lactate production, although, in this case the patient's on going significant disease burden most likely greatly contributed to the rocketing lactate levels seen. Indeed, 24 hours later, his lactate level had jumped to 18.9 mg/dL and the patient expired not long after this.

Another question that arose early in the case was related to the dose of vasopressin. Due to low blood pressure and the already high dose of norepinephrine, I attempted to increase the infusion rate of vasopressin to 0.05 u/min.  The pump had been preprogrammed to disallow this dose. Therefore, I was forced by the pump to limit my infusion to 0.04 u/min.  To me this seemed too low of a dose.  An excellent review of the pharmacology and endocrinology of vasopressin can be located here.  In an early study on vasopressin for septic shock, the dose used to show benefit was 0.07 u/min.  In hemorrhagic shock, it is recommended to use doses near 0.4 u/min and in post cardiac surgery vasodilatory shock a dose of 0.1 u/min is recommended and was found to be devoid of adverse effects. Therefore, evidence exists to allow for higher infusion rates of vasopressin when combined with norepinephrine in a patient in severe shock.

Pre-pro-AVP is synthesized in magnocellular neurosecretory neurons (also known as neurohypophyseal neurons) in the supraoptic and paraventricular nuclei (known as osmoreceptors) of the anterior hypothalamus. It migrates along the supraoptic-hypophyseal tract to the posterior pituitary gland, where it is stored in neurosecretory vesicles and is then secreted in response to decreased stretch on atrial, aortic and carotid body mechano receptors.  Vasopressin acts on receptors labeled V1, V2 and V3. V1 receptors are located on vascular endothelium, kidneys, platelets, and brain and V2 receptors are predominantly located in the kidney collecting duct where they cause an increase in aquaporin insertion in the walls of the collecting ducts to allow increased water reabsorption into the blood.   In refractory shock, the enhanced sensitivity to exogenous vasopressin may be attributable to its ability to block KATP channels, interfere with NO signaling, bind avidly to V1receptors, and potentiate the effects of adrenergic agents at the level of vascular smooth muscle in shock states.

Vasopressin has increased in popularity in ICUs in large part because of large and  well done studies such as VASST, where vasopressin (low dose 0.01 to 0.03 mcg/min) was found to be beneficial (decreased mortality by nearly 10%) in patients with low severity shock [4].  Furthermore, in a post hoc analysis of the data from this large study, Gordon found that patients who received vasopressin were less likely to advance to the loss or dialysis categories of RIFLE scoring system if they already had AKI (21% vs 40%) [5].   Unfortunately, in the VASST study, no difference in mortality could be found in those receiving vasopressin in addition to norepinephrine vs norepinephrine alone in patients with more severe sepsis, as was the case in our patient.

The surgery lasted approximately four hours. The patient received seven liters of crystalloid (LR), 1L of albumin and was essentially anuric.  Blood loss was minimal.  The patient was transported to the ICU ventilated, paralyzed with max pressors continued.  The patients lactate nearly doubled within 24 ours, the INR went to 4, d-dimer went very high, Hgb dropped despite no obvious blood loss, liver enzymes went to nearly 5,000, and K+ levels went to 6.9 mEq/L, while albumin dropped to less than 2 mg/dL. The patient was placed on CRRT and it became obvious that he was not going to survive.  The patient expired on POD #2 after parent multi organ failure with DIC.

1.  Kim HJ, Son YK, An WS. PLoS One. 2013;8:65283
2.  Lee SM, Kim SE, Kim E Bin, Jeong HJ, Son YK, An WS. PLoS One. 2015;10:145181
3. Dünser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, Friesenecker B, Hasibeder WR
Circulation. 2003 May 13; 107(18):2313-9.
4. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D, VASST Investigators.
N Engl J Med. 2008 Feb 28; 358(9):877-87.
5.  Gordon AC, Russell JA, Walley KR, Singer J, Ayers D, Storms MM, et al. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010;36:83–91.
6. Gotmaker R, Peake SL, Forbes A, Bellomo R, ARISE Investigators (2017) Mortality is greater in septic patients with hyperlactatemia than with refractory hypotension. Shock 48:294–300

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)

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.