Case Reports in Anesthesia

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

September 3, 2017

preoperative hypokalemia, replace and proceed or cancel?

The other morning, while I was in the middle of my first of three scheduled cases I received a call from a nurse to report that the K+ level was 2.8 mEq/L on my next scheduled patient.   The patient was a 76 year old female who had a history of Afib, CHF, CAD. Previously, an AICD was placed for unclear reasons.  The patient stated that she believed the reason for the AICD was due to her poor cardiac function.  She reported no history of previous ventricular fibrillation/tachycardia.  She was on diuretics, with oral potassium supplements.

Basic Science review: Potassium homeostasis
Total body stores of K+ are approximately 3000 to 4000 meq with 98% of this located inside the cells.   This concentration differential is maintained by the Na+-K+ ATPase pump, located in the cell membrane which pumps out 3 Na+ ions for every 2 K+ions pumped in.  K+ plays an important role in cell metabolism, and therefore, a myriad of cellular functions deteriorate with an imbalance of K+ ion concentration. For example, significant hypokalemia can result in polyuria due to a reduced sensitivity to ADH.  Also critical is the intracellular to extracellular concentration gradient which largely determines resting membrane potential.

Em=-61 log r[K+]cell+0.01 [Na+]cell / r[K+]ecf + 0.01[Na+]ecf

Alterations in relative concentrations of K+ inside versus outside cells can significantly alter the resting membrane potential leading to cardiac arrhythmia as well as other skeletal muscular symptoms.

The maintenance of whole body potassium  stores is handled by the kidney, in particular by the principal cells of the cortical collecting tubule.  Here aldosterone (secreted in response to a minimal rise in serum potassium) stimulates increased activity of the Na+-K+ ATPase pump located in the basolateral membrane of the principal cell.   This pump pulls K+ from the extracellular space and pumps it into the principal cell while exchanging this for Na+ (3 Na+ : 2 K+ ratio).  As the intracellular K+ ion concentration increases inside the principal cells,  K+ passively leaves the principal cell into the collecting tubule lumen as it follows its concentration gradient. Also in the collecting tubules are located the intercalated cells.  These cells work to reabsorb K+ (exactly opposite the Principal cells).  These cells are particularly important in hypokalemic patients where an H+-K+ ion pump located in the luminal membrane actively exchanges intracellular H+ ions for K+ ions, allowing K+ to be reabsorbed back into the plasma.  As mentioned above, ADH, plays a role in K+ ion secretion by increasing the number of luminal K+ ion channels in the collecting tubules. The K+ ion itself can mimic all of the changes in the kidney that aldosterone initiates.  In other words, elevated K+ levels produce an aldosterone like effect where K+ excretion and Na+ reabsorption are enhanced in the principal cells.  This is due to increased luminal membrane permeability to Na+ and K+ (by increasing the number of open channels for passive diffusion) and increased activity of the Na+-K+ ATPase pump located on the basolateral membrane.

Also critical to K+ homeostasis is the urine flow rate in the cortical collecting tubule.  There are two mechanisms that allow a greater urinary flow rate in the cortical collecting tubule to increase net K+ secretion leading to hypokalemia.  1) increased flow lowers the intraluminal (inside the collecting tubule) K+ concentration, favoring the passive movement of K+ out of the principal down its concentration gradient via the K+ channels in the luminal membrane of the principal cells. 2) increased flow through the kidney brings more Na+ to the collecting tubule leading to increased Na+ reabsorption in the collecting tubule causing the lumen to become more electronegative favoring passive K+ diffusion to maintain electroneutrality.  Furthermore, as more Na+ is reabsorbed into the principal cell, the Na+-K+ ATPase pump removes the Na+ from the cell back into the body, leading to increased K+ entry into the principal cell which increases the intracellular K+ concentration of the principal cells of the collecting tubule. Increased distal flow of urine in the collecting tubule seems to be the mechanism by which the loop and thiazide diuretics induce hypokalemia. These agents increase distal flow by diminishing Na+ and water reabsorption in the loop of Henle and distal tubule respectively.

Clinically, chronic K+ alterations from so called normal levels are not as likely to cause outward clinical symptoms.  This is because, the intracellular to extracellular gradient is the more important than the overall measured serum concentration.   Nevertheless, hypokalemia does result in symptoms even if chronic in nature.  When considering the hypokalemic patient in the immediate preoperative period, it is important to consider three main things:  1)  degree of hypokalemia, 2) Invasiveness of surgery and 3) patient's co morbid conditions (i.e. concomitant coronary artery disease or congestive heart failure).   Per Miller’s Anesthesia, p. 1107, “As a rule, all patients undergoing elective surgery should have normal serum potassium levels.  However, we do not recommend delaying surgery if the serum potassium level is above 2.8 mEq/L or below 5.9 mEq/L, if the cause of the potassium imbalance is known, and if the patient is in otherwise optimal condition.”

Patients without underlying cardiac disease are unlikely to suffer myocardial effects, even at levels below 3.0 mEq/L. However, those with ischaemic heart disease, heart failure or left ventricular dysfunction are at risk of arrhythmias with only mild or moderate hypokalaemia. This fact was highlighted in 1981 when Hulting followed patients admitted for treatment of an MI.  This paper showed that patients who had a baseline risk of arrhythmia of 3.5% increased to 8% if their serum K+ was less than 3.5 mEq/L. They also found that no patients suffered arrhythmias if their serum potassium was greater than 4.6 mEq/L.

In patients undergoing very quick surgeries such as cataract, egd, etc, it is routine to not check labs in the first place so that hypokalemia if it existed would be unknown to the provider.  In patients who require diuretics undergoing intermediate or high risk surgery, checking potassium levels is common and hypokalemia should prompt a decision tree based on the degree of hypokalemia, patient co morbidities, and type of surgery.

By far the most common cause of hypokalemia in the preoperative period is diuretic use. Diuretic induced hypokalemia has been associated with an increased rate of arrhythmias [4]. Furthermore, diuretic therapy in hypertension and heart failure has been associated with an increased rate of arrhythmic death that can be prevented by a K+ sparing diuretic and therefore, may be related to K+ depletion [5,6].  In the Framingham Heart Study [10], they reported increased frequency of PVCs to be associated with hypokalemia.   They estimated that the arrhythmia increased by 27% wit each 0.5 mEq/L decrease in K+ level. Understanding diuretic physiology makes sense given its importance in both inducing and treating hypokalemia.  A brief primer on diuretics follows:

Loop Diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid)

  • may lead to the excretion of 20 to 25% of filtered Na+ at max doses.
  • Act in thick ascending limb of loop of henle. 
  • loop diuretics inhibit Na+ reabsorption by binding to Cl- site of the Na+-K+-2Cl- carrier on luminal membrane.  The carrier only works when all four sites are occupied.
  • Secondarily inhibit Ca2+ reabsorption which is passive down an electronegative gradient by the absorption of Na+/K+, which leads to a caliuresis.
  • Ca2+ effects make loop diuretics excellent method of treating hypercalcemia when combined with saline loading.
Thiazide type diuretics

  • primarily inhibit NaCl transport in the DCT
  • at max doses only inhibit up to 3 to 5% of filtered Na+ (far less potent than loop diuretics).
  • Diuresis offset by increased reabsorption in the cortical collecting tubule.
  • Thiazide type diuretics also compete with Cl- at the Na+-Cl- cotransporter
  • In contrast to loop diuretics, thiazide type diuretics can increase the reabsorption of Ca2+ in the DCT and early collecting tubule which may be useful in the treatment of recurrent kidney stones due to hypercalciuria.
Potassium Sparing Diuretics (Amiloride, Spironolactone, Triamtere)

  • Act in principal cell in the cortical collecting tubule where Na+ reabsorption occurs passively through Na+ channels (which are increased via aldosterone)
  • amiloride and triamterene directly decrease the number of open Na+ channels decreasing Na+ reabsorption leading to decreased K+ (and H+) secretion.  
  • Spironolactone competitively inhibits aldosterone resulting in same result.
  • Weak natriuretic effect (1 to 2% of filtered Na+).
  • Amiloride is very effective in the treatment of polyuria/polydipsia from lithium-induced nephrogenic diabetes insipidus where the tubular cells of the collecting ducts become insensitive to ADH from the accumulation of lithium.
  • Triamterene is a potential nephrotoxin, possibly leading to crystalluria and cast formation which in severe cases has lead to renal failure particularly if given in conjunction with NSAIDs.

 In a patient with hypokalemia not taking any loop or thiazide diuretics, other causes should be considered.  The next most common cause would be increased GI losses, either from diarrhea, vomiting or NG suction.  Magnesium levels should also be checked.  The loop and thiazide diuretics also result in Mg2+ wasting, and hypomagnesemia promotes K+ wasting. The mechanism whereby Mg2+ effects K+ homeostasis is unclear.  However, replacement with MgSO4 (as is common in the perioperitve period) could be problematic.  The sulfate acts as a non resorbable anion in the collecting tubule (leading to a greater negative intraluminal charge).  The negative charge in the lumen prevents the passive diffusion of K+ out of the lumen into luminal cells of the collecting tubules leading to increased K+ losses. Repletion with magnesium chloride or magnesium lactate would avoid this problem. 

In the patient who is hypokalemic prior to anesthesia, it is important for the anesthesiologist to consider all of the ways in which acute shifts of K+ into the intracellular space may occur exacerbating the pre existing hypokalemia.  Avoidance of respiratory or metabolic alkalemia. is very important since alkalemia results in a transfer of H+ ions from the intracellular space into the plasma to counter act a rising pH.  To preserve electroneutrality, Na+ and K+ ions  enter cells.  In general the plasma concentration falls less than 0.4 meq/L for 0.1 unit increase in pH.  Therefore, a patient with a serum potassium of 3.1 meq/L who develops a respiratory alkalosis to a pH of 7.5 due to inadvertent hyperventilation, will potentially see an acute intracellular shift of K+ ions leading to a serum K+ concentration of 2.7 meq/L. 

Insulin directly stimulates the entry of K+ ions into skeletal muscle and hepatic cells via a Na+-K+ ATPase pump. Thusly, it would be important to avoid using a dextrose solution to replace potassium, as the dextrose can stimulate insulin release causing a paradoxical further decrease in the serum potassium concentration.

The Na+-K+ -ATPase pump is also stimulated by beta 2 adnergic receptors.  This is a particular concern in the preoperative period when stress related events causes a surge in catecholamines. In fact, a catecholamine surge can acutely lower the plasma K+ concentration by approximately 0.5 to 0.6 meq/L.  This large change in serum K+ ion concentration may be partially due to the effects of insulin which is secreted in response to increased B2 adrenergic activity. Prompt recognition of this may be treated by adequate opioids +/- non selective beta blockers (i.e. propranolol). Administration of beta agonists such as albuterol for a breathing treatment, may induce a 0.5 to 1 meq/L drop in serum K+ concentration.

Clinical studies looking at preoperative K+ levels and patient outcomes

One study done on patients with coronary artery disease who underwent non-cardiac surgery suggested that a pre-operative serum potassium level of less than 3.5meq/ L was independently associated with peri-operative mortality. Other studies have failed to find any increased incidence of arrhythmia in patients at high risk (major vascular or cardiac surgery with cardiac disease) who also had significantly decreased K+ levels [2].  However, this study was probably under powered.  They examined only 447 patients, and of these only 9% had significant hypokalemia (less than or equal to 3.0 mEq/L). In contrast to this, another study of 2402 patients undergoing CABG, were followed for a variety of outcomes.   In this study, a serum potassium level less than 3.5 mEq/L was a predictor of serious perioperative arrhythmia (OR 2.2), intraoperative arrhythmia (OR 2.0) and post operative atrial fibrillation/flutter (OR 1.7) [8].  In another study looking at patients undergoing non cardiac surgery were analyzed for predictors of preoperative myocardial infarction (PMI) or cardiac death. They found that  among several risk factors hypokalemia (serum level less than 3.5 mEq/L) was identified as a predictor of these outcomes [9]. Myocardial ischemia seems to be a significant risk factor  leading to arrhythmias in the setting of hypokalemia [3,7]. Therefore, it becomes particularly important to monitor potassium levels in any patient at significant risk for preoperative ischemia.

Repletion of K+ prior to surgery is fraught with problems due to the logistics of K+ administration.  KCl is painful in peripheral IVs and can cause severe phlebitis.  In my patient, she could not tolerate KCl being infused in her peripheral IV at a concentration of 20 mEq per 100 mL any faster than 50 mL per hour (or 20 mEq per 2 hour time period).  Therefore, it was decided to delay surgery until later that afternoon to allow adequate time for her to receive 40 mEq (requiring 4 hours) and to recheck her potassium level.  After 5 hours, we returned to perform her surgery.  Her repeat potassium was 3.3 mEq/L.  She underwent GETA with Sevoflurane.  Because she had a medtronic AICD, defibrillator pads were placed prior to surgery and a magnet was placed over the device to disable anti tachycardia therapy.  The anesthetic was uneventful and she was observed overnight in the hospital.

1.  Shah, K.B., Klienman, B.S., Rao, T.L., Jacobs, H.K., Mestan, K. and Schaafsma, K. (1990) Angina and other risk factors in patients with cardiac diseases undergoing non-cardiac operations. Anesth. Analg., 70, 240-247. 

2.Hirsch IA1Tomlinson DLSlogoff SKeats AS.   1988 Feb;67(2):131-6.
3.  Hulting, J. (1981) In hospital ventricular fibrillation and its relation to serum potassium. Acta Med. Scand. Suppl., 647, 109-116.
4. Kuller LH, Hülle SB, Cohen JD, Neaton J. Circulation 73:114, 1986
5. Siscovick DS, Raghunathan TE, Psaty BM, et al. N Engl J Med 330:1852, 1994
6. Pitt B, Zannad F, Remme WJ, et al. N Engl J Med 341:709, 1999
7. Nordrehaug JE, von der Lippe G. Hypokalaemia and ventricular fibrillation in acute myocardial infarction.  Br Heart J.1983;50:525-529.
8. Wahr JA, Parks R, Boisvert D et al. JAMA 1999; 28(23):2203-10.
9. Shah KB, Kleinman BS, Rao TL, Jacobs HK, Mestan K, Schaafsma K.  Anesth Analg.1990;70:240-247.
10. Tsuji H, Venditti FJ Jr, Evans JC, et al. Am J Cardiol 74:237, 1994

May 10, 2017

35 year old female with history of alcohol abuse

The other day a 35 year old female presented for surgery for lipoma excision from the posterior neck.  She reported a history of severe alcohol abuse in the past for which she was taking naltrexone 100mg qd.  The patient also reported a severe allergy to all steroids.  When I asked for details, she reported that she had severe manic exacerbations with steroids and that this had happened with a one time dose given prior to surgery in the past.  The patient had also experienced at least two seizures in the past, one occurring after surgery.  She was told that this seizure could have been related to the anesthetic she had.  She also reported another seizure episode in the past related to severe depletion of vitamin B12.  She was taking several medications for anxiety, bipolar, alcoholism and PTSD.  These included:

  • Seroquel
  • Tegretol
  • Prozac
  • Prazosin
  • Klonipin
In addition, the patient was concerned because in the past, she had experienced very severe and  unpleasant emergence anxiety and agitation.

There were several issues that played a role in choosing an anesthetic for this patient. First she requested that she did not receive a steroid which I commonly give to female patients (especially non smokers) as they are at increased risk for PONV.  In addition, She was medicated with naltrexone for alcoholism.  Therefore, there was likely to be challenges with pain control in this patient.  Lastly, the patient had had previous seizures following anesthesia during emergence as reported.  She was on a number of medications that could potentially also activate her liver enzymes causing her to be a rapid metabolizer of anesthetics such as propofol, midazolam and fentanyl.

This patient described a past experience of severe agitation and anxiety upon emergence.  Emergence delirium (ED) is not uncommon in pediatrics. However, it has not been well studied in adults.  One review of the literature  estimated an incidence of 3% in adult patients. Another study found an incidence of 4.7% among adult patients [1].  However, in those at risk for PTSD an incidence of 20% is more likely [3].  Emergence delirium in adults can be a significant problem as they are capable of self injury.  A recent case report details a severe episode of emergence delirium in a patient with PTSD [4], and subsequent case where changes were made to help mitigate this issue.  In this patient with a self described episode of emergence delirium and history of PTSD and bipolar disorder, several considerations would be important.  One consideration is the recommendation to avoid midazolam in particular in this patient group.  Some literature suggests that Midazolam in particular can enhance the memory of events surrounding the trauma [5].  If a benzodiazepine is desired, lorazepam may be preferred.  While it has been traditional teaching that ketamine can excerbate PTSD, and should be avoided during anesthesia in these patients, recent literature suggests that ketamine may not be a problem [6], or may be helpful in the prevention of PTSD [7].  Currently, prazosin, an alpha 1 blocker is used in the treatment for PTSD, but also is effective in the treatment in reducing alcohol intake in alcoholics.  Therefore, it would be important to verify that this patient continued to take this medication on their usual schedule prior to anesthesia. Prazosin, as an alpha 1 blocker, can cause sudden drops in blood pressure, and this is particularly problematic when patients stand up suddenly.  In pediatrics, there is quite a large amount of literature looking at interventions that can prevent or decrease the chances of ED. Propofol decreased the incidence from 38% after sevoflurane to 0% in pediatrics.  In the pediatric literature, other studies have corroborated the benefit of propofol in reducing ED. In adults, propofol also was able to decrease the incidence of ED, from 45% to 10% [10]. Another study in the pediatric literature showed that 2 mck/kg of IV Clonidine after induction significantly reduced the incidence of ED. Like Clonidine, Dexmedetomidine may also be a useful (although expensive) adjuvant to help prevent ED.  Given that the patient had already experienced a significantly negative ED event in the past, had a post anesthetic seizure, and was also allergic to steroids, so that decadron was unavailable for PONV prophylaxis, I opted to utilize a propofol infusion for anesthesia maintenance.  Unfortunately, in a patient taking naltrexone for alcoholism, maintaining anesthesia with routine anesthetic dosages could be fraught with problems.  Therefore, I opted to utilize a BIS monitor as an aid in verifying the depth of anesthesia. The BIS system is a proprietary system using data from a processed EEG signal to produce a dimentionless number that correlates with the depth of anesthesia in a sense. It is presumed that a number between 40 and 60 represents general anesthesia and would thus have a low incidence of recall.  It is not clear if an alcoholic or patient who is taking naltrexone will respond in the same fashion to a typical anesthetic.  In this patient, 200 mg of propofol was given for induction along with 100 mcg of fentanyl and 2 mg of versed.  The BIS went from 87 to 34.  This change in BIS was as expected.  Shortly thereafter, with an infusion of propofol running at 200 mcg/kg/min and the BIS reading 34, an injection of local anesthetic by the surgeon was performed at the site of the lipoma.  The patient immediately started moving requiring an additional bolus of propofol and another 100 mcg of fentanyl.  This would be an atypical response at a BIS of 34.  However, given that propofol does not inhibit spinal reflexes like the potent inhalational agents, this could be considered within normal limits.  Given the patient movement at a BIS of 34, the BIS was maintained in the high 30's for the remainder of the very short case.  A propofol infusion of 200 mcg/kg/min was sufficient.  after 30 min the case was over and the BIS reading was 36.  The propofol infusion was discontinued and in 4 minutes, the BIS had jumped from 36 to 74 and the patient began responding to commands and was extubated.   This rapid emergence could likely be explained by rapid hepatic metabolism of the propofol as well as residual naltrexone binding of mu opioid receptors decreasing the efficacy of fentanyl.  The patient was transported to the PACU with no evidence of emergence delirium and seemingly in good spirits with good pain control.  However, 30 minutes later the PACU nurse called me to report that she had given an additional 200 mcg of fentanyl in PACU for pain control and the patient was reporting 10/10 pain.  This was unusual in that the small lipoma excision had been anesthetized with local anesthetic.  Hydromorphone was ordered and no more calls were forthcoming.

Currently there is an epidemic occurring in America with opioid abuse.  It is becoming ever more likely that we will be required to care for one of these patients. Many of these patients will require therapy such as suboxone to prevent cravings of opioid.  Suboxone is a combination of buprenorphine and naltrexone where  the ratio is 4 parts buprenorphine to 1 part naltrexone.  The naltrexone is included to prevent the crushing and snorting or intravenous injection and is not considered to be active when suboxone is taken as intended. Buprenorphine is a partial agonist at the mu receptor.  It is also a kappa antagonist. These receptors are predominantly located in the spinal cord.  As a partial agonist, buprenorphine has a ceiling affect which occurs at about 32 mg / day.  Most patients who are on buprenorphine (suboxone) for maintenance therapy, are on doses that are higher than for treatment of chronic pain (i.e 16 mg for maintenance vs 2 to 4 mg for chronic pain therapy). There are two issues that anesthesiologists need to understand when patients arrive for surgery on suboxone.  First is the underlying pharmacokinetics.  Suboxone, if provided as a patch takes a full seven days to clear.  Buprenorphine is also prescribed to be taken sublingual where the bioavailability is  30 to 50%. The half life of high dose buprenorphine (as used for maintenance therapy in opioid dependent patients)  is 20 to 70 hours. However, the half-life is highly variable and depends on patient characteristics as well as the dosing regimen. It is clear from case reports that maintaining suboxone in the preoperative period will lead to very poor pain control amid escalating pure mu opioid agonist requirements. For elective surgery, where significant post op pain is anticipated, it is recommended that patients discontinue suboxone therapy for five days.  In urgent/emergent surgical patients presenting on suboxone maintenance therapy, it may be very difficult to override the suboxone from the mu receptor. The reason for this difficulty is a result of the very high affinity for the mu opioid receptor by buprenorphine.  It has been noted that buprenorphine binds the mu receptor avidly, and only slowly diffuses away.  Therefore, the mu receptor remains unavailable to pure mu agonists. Consequently,  respiratory depression is a risk at the very high dosages required to achieve pain control.  It may be wise to titrate a rapid onset opioid (fentanyl) prior to surgery in the operating room to help anticipate what dose the patient may tolerate or require for post op pain control.  Suboxone should not be given during the preoperative period to avoid precipitating additional pain.  For patients where post op pain is anticipated to be minor or mainly controlled via other means (i.e. local anesthetics) suboxone may be continued in the preoperative period.
My patient was on naltrexone.  As a mu antagonist, it was anticipated that override might be difficult.  While, indeed, higher doses of fentanyl than typical were required, the requirements were not extraordinary.  Once again, an understanding of pharmacokinetics is important to determine how difficult it might be to override any naltrexone present at the mu receptor.  A single oral dose of 25 mg of naltrexone has an apparent half-life (t1/2) of 14 hours. Veberey et al. [2], looked at naltrexone effectiveness in blockade of heroin 25 mg. After a 100 mg oral dose of naltrexone, there was 96% blockade at 24 hours, 86.5% blockade at 48 hours, and 46.6% at 72 hours. Therefore, it would seem prudent to recommend that patients avoid naltrexone for 72 hours prior to any surgery where it is anticipated post op pain control will require opioid therapy.  In patients who have chronically taken naltrexone for maintenance therapy, there is up regulation of mu receptors in the brain [8]. Therefore, patients who discontinue naltrexone, may be resistant or more susceptible to opioids depending on how much naltrexone remains in the system compared to the degree of mu opioid receptor upregulation.  While naltrexone is a mu opioid antangonist, it is approved by the FDA for treatment of alcoholism because it reduces the euphoria and positive reinforcing effects of ethanol use [9].
Lastly, this patient had a history of vitamin B12 deficiency.  Vitamin B12 is an integral part of two biochemical reactions: the conversion of L-methylmalonyl coenzyme A into succinylcholine coenzyme A and the formation of methionine by methylation of homocysteine.  These reactions are critical for the synthesis of DNA and to the maintenance of the myelin sheath by methylation of myelin basic protein. Active Vitamin B12 contains cobalt in its reduced form (Co+).  Nitrous oxide produces irreversible oxidation to the Co++ form leading to inactive Vitamin B12. The result is an irreversible inactivation of the enzyme methionine synthase  There are several case reports in the literature of patients developing subacute combined degeneration of the spinal cord following nitrous oxide anesthesia [11,12,13].  In these case reports, the diagnosis of subacute combined degeneration of the spinal cord was made several weeks post op after otherwise routine and uneventful anesthesia. Subacute combined degeneration of the spinal cord is characterized by degeneration of the posterior and lateral columns.   The avoidance of nitrous oxide in patients with anemia of unknown cause or in patients at risk of vitamin B12 depletion is recommended.   A significant risk factor for Vitamin B12 depletion is alcoholism for two reasons. 1) alcohol abuse leads to poor nutrition and therefore, vitamin B12 intake is reduced, and 2) excessive alcohol use leads to atrophic gastritis.  Atrophic gastritis is characterized by inflammation and dysfunction on the cells lining the stomach so that production and secretion of intrinsic factor is compromised.   Intrinsic Factor (IF) is essential for the absorption of vitamin B12.  Atrophic gastritis also decreases the production of hydrochloric acid. The increase in pH leads to overgrowth of different bacterial strains that consume vitamin B12 and reduction in efficiency of food breakdown that is necessary for the release of vitamin B12 from the diet for absorption into the body.

Lastly, her seizure episode following anesthesia should be addressed more fully in context of her history of alcoholism.  While there are case reports of severe vitamin B12 deficiency leading to seizures, this isn't typical.  What  is more common in alcoholics undergoing surgery is alcohol withdrawal syndrome (AWS). AWS can result in an incidence of mortality of around 15% if untreated [14]. In patients who abuse alcohol, AWS more commonly manifests during stress such as surgery [15]. It has been suggested that in operative patients, hypotension, hypoxia, or uncontrolled pain in the PACU may precipitate AWS [16].  The key features of AWS include hyperexcitability of the CNS due to reduced GABA activity and increased glutaminergic action [17]. Increased noradrenergic activity can lead to hypertension, tachycardia, sweating, tremor, and hallucinations.  Lastly, seizures can occur. Seizures typically occur early in the process, i.e. 6 to 8 hours after stopping alcohol intake. This is long before the most severe manifestations of AWS, which may take 3 to 4 days. Attributing this patient's prior post anesthetic seizure to AWS may be reasonable, but can't be proven.

In conclusion, this patient had multiple medical issues that were impactful on making an anesthetic plan.  These included a history of seizures related to anesthesia and vitamin b12 depletion, alcoholism treated with naltrexone and prazosin, as well as high anxiety with a  history of severe emergence delirium requiring treatment.  In this patient, using TIVA, local anesthesia for the surgery site, along with a BIS monitor allowed for an uneventful anesthetic and emergence.

1. Lepouse c et al.  Emergence delirium in adults in the post-anesthesia care unit, BJA, 2006, vol. 96(6), 747-53.
2. Verebey K. The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics. NIDA Res Monogr 1981;28: 147-58.
3. Curtis D, Stevens WC. Recovery from general anesthesia. Int. Anesthsiol. Clin, 1991;29(2):1-11.
4. Lovestrand D, Phipps S, and Lovestrand S.  Posttraumatic stress disorder and Anesthesia Emergence.    AANA Journal, 2013(81).3. 199-203.

5. McGhee LL, Maani CV, Garza TH, DeSocio PA, Gaylord KM, Black IH. The relationship of intravenous midazolam and posttraumatic stress disorder development in burned soldiers. J Trauma Inj Infect Crit Care. 2009;66(4 suppl):S186-S190 
6.  Wilson JT, Pokorny ME. Experiences of military CRNAs with ser- vice personnel who are emerging from general anesthesia. AANA J. 2012;80(4):260-265.
7.  McGhee LL, Maani CV, Garza TH, DeSocio PA, Gaylord KM, Black IH. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma Inj Infect Crit Care. 2008;64(2 suppl):S195-S199.
8. Yoburn BC, Luke MC, Pasternak GW, Inturrisi CE. Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE. Life Sciences 1988;43: 1319-24.
9.  Volpicelli JR, Alterman AL, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psych 1992;49: 876-80
15. C. Spies, H. Tønnesen, S. Andreasson, A. Helander, and K. Conigrave, “Perioperative morbidity and mortality in chronic alcoholic patients,” Alcoholism, vol. 25, no. 5, pp. 164S–170S, 2001. 

August 9, 2016

elevated preoperative BNP, what do I do now?

A rather unhealthy and unkept gentleman of about 54 years of age presented to the ER after a 'fall'.  He presented to the preop area as an add for intertrochanteric nail by our friendly orthopedic surgeon.

I was assigned the case and went over to look through the chart.

I noted a cardiology note that indicated that his troponin levels were very slightly elevated and an echocardiogram was recommended by the cardiology NP. Since this gentleman, had an injury that was better treated sooner than later (more discussion on this below), and he did not have an EKG with any indication of ischemia, I was not convinced that delaying his surgery for an additional day to perform an echo was absolutely required.  I continued to look for more information to determine the liklihood that an his slight bump in troponins represented something truly sinister, or was perhaps more benign in nature.  It was known that he was likely homeless, dehydrated, and had a mild elevation in his BUN and creatinine consistent with pre renal azotemia in a dehydrated (hypovolemia) patient.

A further review of his chart revealed that he also had a BNP of over 1200 pg and lasix had been ordered by the ER physician, but not yet administered due to various logistical issues.  At this point, I decided to call the Ortho surgeon and have a conversation with him.  After discussing it with him, a decision was made to cancel the surgery until his volume level could be better determined, and optimized.
Patients in heart failure are poor candidates for surgery.  Post operative morbidity and mortality is significantly higher; and any elective surgery is contraindicated when if patients are in failure.  is predictor of poor outcome in non cardiac surgery.  Typically, it is best to post pone non emergent surgery in patients suspected or known to be in hear failure.  Unfortunately, clinical signs of heart failure (dyspnea, jugular vein distention, leg swelling etc) are not perfect indicators of a patient's status.  Current evidence suggests that hip fracture patients have better outcomes when the fracture is repaired within 24 hours of admission.  Therefore, an anesthesiologist who makes a decision to delay hip fracture surgery may potentially increase overall  risk to the patient in an attempt to improve the patients perceived short term risks.

Atrial Natriuretic Peptide (ANP) was originally isolated from rat atrial myocardium. In humans, it is secreted predominantly by atrial myocytes.  BNP was subsequently isolated from porcine brains. In humans it is secreted by both atrial and ventricular myocytes, but it is predominantly the ventricular myocytes that secrete BNP. These natriuretic peptides have several functions in normal physiology. When cardiac myocytes are stretched due to increased load or volume, secretion of these peptides results in: 1) down regulation of the sympathetic nervous system, and the renin-angiotensin-aldosterone system, 2) improved natriuresis and diuresis via afferent and efferent hemodynamic mechanisms of the distal tubule of the kidney, 3) decreasing peripheral vascular resistance via relaxation of smooth muscle. A BNP precursor is secreted by left ventricular myocytes which is synthesized into proBNP.  This short lived molecule is cleaved into the biologically active C terminal portion and biologically inactive N-terminal (NT-proBNP) portion.

In a observational study, BNP was found to be an independent predictor of increased cardiac events after non cardiac surgery and performed better than a preoperative scoring system after abdominal surgery [1].
It is known that BNP levels correlate with demodynamic parameters such as right atrial pressure, PCWP, and left ventricular end diastolic pressures.   Echo studies looking at the correlation of BNP levels with ventricular function have also been done.  Usuing the NYHA classificaiton system we find that in class I, BNP averages 240 pg, II 390 pg, III; 640 pg and IV 820 pg.  This indicates that higher levels do seem to correlate with more significant cardiac dysfunction.

In 2002, the national breathing not properly (BNP) trial was completed and was able to show that plasma BNP measurement was able to differentiate between CHF  and non CHF causes of dyspnea (area under receiver operating characteristic curve = 0.91) [2]. In this trial, a single BNP measurement was also more accurate than two commonly used methods of determining cardiac causes of SOB, the National Health and Nutritional Examination score and Franghiham (see below).

Using data from this same study, a patient presenting with SOB, and a BNP less than 50 pg/mL has an 7% chance that the cause is heart failure. If the BNP is between 50 pg/mL and 150 pg/mL, the chance that heart failure is the causes rises to 36%.  With a BNP of greater than 150 pg/mL, there is an 83% chance of heart failure. Later, another study concluded that if the BNP level was less than 100 pg/mL, there was a low liklihood for congestive heart failure.  Alternatively, in this study, they concluded that blood levels greater than 500 pg/mL made a diagnosis of heart failure extremely likely [3].

In another smaller study, dao et al. showed that a BNP of less than 80 pg/mL had a 98% negative predictive value. In this same trial, patients  with dyspnea and diagnosed with CHF had a mean BNP of 1076 pg/mL while patients who had dyspnea but were found not to be in heart failure had a mean BNP of only 38 pg/mL.  
A study of patients undergoing non cardiac surgery found that an elevated BNP measurement was an independent predictor of postoperative cardiac events. In this study, BNP measurements outperformed the goldman multifactorial clinical index in predicting cardiac adverse events after non cardiac surgery.  (fee figures below for a great summary of this study).

They showed that a BNP level of 0 to 100 pg/mL had zero risk,  BNP levels of 201-300 pg/mL was considered low risk (5% event rate),  intermediate risk (12% event rate) was from 200 to 300 pg/mL, and high risk (greater than 300 pg/mL) had an event rate of 81% [4]. This was followed up with another study that was able to demonstrate that BNP levels greater than 40 pg/mL was associated with a seven fold increase in cardiac events in the early post operative period and longer hospital stay [5]. Yeh et al. found that pre operative NT pro-BNP independently predicted cardiac complications in non cardiac surgery (greater than 450 ng/L) with 100% sensitivity and 83% specificy [6].

The clinician should recognize that there are several causes other than heart failure that can result in elevated BNP levels.  These include renal failure (decreased clearance), pulmonary embolism, pulmonary hypertension, and chronic hypoxia.  Furthermore, BNP increases along with age. A trial was able to determine five independent predictors of elevated BNP in patients without heart failure.  They were 1) low hemoglobin values, 2) low BMI, 3) history of A fib 4) radiographic cardiomegaly, and 5) advanced age. This is why this test has been found to have very good sensitivity, but not great specificity.  Put another way, if the BNP is normal, the clinician has very high confidence that the patient is not currently in CHF or that cardiac complications will be low.  However, the opposite is not true; if the BNP is elevated, the clinician cannot be as confident that the case should be cancelled or delayed because of certain CHF in the patient.  However, ruling out the above other causes of elevated BNP can aid the clinician in ruling out other sources of an elevated BNP.

BNP also tracks appropriate therapy.  Therefore, patients being treated with ACE inhibitors and diuretics will have lower than typical BNP levels, while other medications may increase BNP (beta blockers and digoxin).

Unfortunately, at this point, rigorous testing in the preoperative setting to determine cut off points for BNP levels in order to determine whether cases should be cancelled or not have not been done.  In "up to date" the following quote relays the current recommendations regarding the use of BNP in the preoperative period to aid in evaluation of the patient: "However, it is unknown whether or which changes in perioperative management would improve outcomes in surgical patients with elevated BNP or NT-proBNP levels".

Determining when to delay or cancel hip fracture surgery is often a challenge for the anesthesiologist. Particularly since this population of patients generally have significant co morbidities that would result in cancelation or delay in purely elective surgery.  Orthopedists are becoming more aggressive in trying to bring their patients to surgery within 24 hours of injury because of numerous observational trials indicating that early hip fracture surgical repair leads to better functional outcome and lower rates of complications and mortality. In fact, current guidelines recommend surgery within 24 hours of injury [6].  Early surgery has also been included as a quality marker in the highly disseminated set of Inpatient Quality Indicators from the Agency for Healthcare Research and Quality [7].  So, would my patient be better off, overall,  if I had administered lasix in the holding area, and proceeded to surgery within the next 30 minutes to hour?
Observational trials are prone to selection bias, attrition and detection bias.  Prospective observational trials are more robust generally than retrospective trials, but a recent systematic review found that currently, 65% of studies addressing this issue are retrospective, and therefore, subject to confounding and biased ascertainment of outcomes. One of the most obvious problems with retrospective observational trials is that patient who are sicker are more likely to be delayed and therefore, have a larger time delay between the injury and the surgery.  Therefore, it is likely that patients will have better outcomes in the 'early' surgery group vs. the later surgery group because the early surgery group is a healthier cohort.  As an example, a recent large [8] retrospective observational trial in Spain looked at over 81,000 patients who had hip fracture surgery.  They found a positive correlation with early surgery and lower in hospital mortality.  However, after correcting for a multitude of variables, they found that indeed, patients at much higher risk had delayed surgery, and after correcting for this, there was no longer any effect on mortality from delaying surgery.  In another study, the authors were able to demonstrate that individualizing the timing of surgery to medically optimize patients at higher risk led to improved outcomes [9]. Vidan et al. and Khan et al also showed that when controlling for medical co-morbidities, timing of surgery ceased to be a factor in mortality difference between groups [10,11]. Still, while it seems difficult to say that mortality is improved with early surgery after injury (within 24 hours), other important metrics may be apt for improvement.  Investigators have found that time to discharge was 10.9 days earlier  if surgery is performed within 48 hours [12], and another study concluded that surgery within 24 hours decreased LOS by 4 days [13].  Other clinically relevant benefits found with early surgery include a decrease in the incidence of decubitus ulcer formation and an increased likelihood of return to independent living.
In summary, at this point, due to lack of prospective RCTs, it is not clear that early surgery (within 24 to 48 hours of injury) can reduce mortality.  However, other parameters, such as LOS, pressure ulcer formation and long term functional recovery may be improved by early surgery.  While guidelines recommend that patients go to the OR for operative repair within 24 to 48 hours of injury, the anesthesiologist should feel confident that a delay in surgery to allow for medical optimization of severe evolving medical conditions is warranted.  Each case should be judged by its own merits and the anesthesiologists should play a role in not obstructing early surgery unless truly necessary. As an example, I recently reported on a case where a patient with a hip fracture was admitted for operative repair, but the gastroenterologist recommended a transfer because the patient had severe liver dysfunction.  The orthopedist called me and I recommended proceeding with surgery given the enormous delay caused by a transfer and lack of evidence that further optimization could improve the patients outcome.  This case proceeded as scheduled, although, the gastroenterologist, inked in the chart that he recommended a spinal which created a medico legal issue for the anesthesiologist.

1. Mercantini P, et al. Preoperative brain natriuretic peptide (BNP) is a better predictor of adverse cardiac events compared to preoperative scoring system in patients who underwent abdominal surgery.  World J Surg 2012 Jan;36(1):24-30.
2. Maisel AM, Krishnaswamy P, Nowak R, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure: primary results from the Breathing Not Properly (BNP) Multinational study. Paper presented at: 51st Annual Scientific Session of the American College of Cardiology;March 17–20,2002; Atlanta, Ga.

  • 3. Mueller C
  • Scholer A
  • Laule-Kilian K
  • et al
  • Use of B-type natriuretic peptide in the evaluation and management of acute dyspneaN Engl J Med 2004;350:647-54.

    1. 4.  Dernellis J
    2. Panaretou 
    Assessment of cardiac risk before non-cardiac surgery: brain natriuretic peptide in 1590 patients. Heart 2006;92:1645-50
    1. 5. Cuthbertson BH
    2. Amiri AR
    3. Croal BL
    4. et al
    The utility of B-type natriuretic peptide in predicting perioperative cardiac events in patients undergoing major non-cardiac surgeryBr J Anaesth 2007;99:170-6.Yeh HM, Lau HP, Lin JM, et al. Preoperative plasma N-terminal pro-brain natriuretic peptide as a marker of cardiac risk in patients undergoing elective non-cardiac surgery. Br J Surg2005;92:1041–5
    6.  Fractured neck of femur. Prevention and management. Summary and recommendations of a report of the royal college of physicians.  J R Coll Physicians Lond 1989 Jan:23(1):8-12
    7. Department of Health and Human Services. Agency for Healthcare Research and Quality: AHRQ Quality Indicators. Guide to Inpatient Quality Indicators: Quality of Care in Hospitals - Volume, Mortality, and Utilization. Version 3.1, March 12, 2007
    9.  Zagrodnick J, Kaufner HK. Decreasing risk by individualized timing of surgery of para-articular femoral fractures of the hip in the elderly.
    10.  Vidán MT, Sánchez E, Gracia Y, Marañón E, Vaquero J, Serra JA.. Causes and effects of surgical delay in patients with hip fracture: a cohort studyAnn Intern Med. 2011;155(4):226–233
    11.  Khan SK, Kalra S, Khanna A, Thiruvengada MM, Parker MJ.. Timing of surgery for hip fractures: a systematic review of 52 published studies involving 291,413 patientsInjury. 2009;40(7):692–697
    12. Siegmeth AW, Gurusamy K, Parker MJ.. Delay to surgery prolongs hospital stay in patients with fractures of the proximal femurJ Bone Joint Surg Br. 2005;87(8):1123–1126
    13. Al-Ani AN, Samuelsson B, Tidermark J, et al. . Early operation on patients with a hip fracture improved the ability to return to independent living. A prospective study of 850 patientsJ Bone Joint Surg Am. 2008;90(7):1436–1442

    July 25, 2016

    cysto after laparoscopic surgery to verify ureter patency

    A 37 year old female presented for diag laparoscopy for suspected ectopic pregnancy and mass in the left adnexa.

    The procedure was uneventful, however, the surgeon was unable to visualize the ureters after performing a left salpingectomy.  She was concerned about the ureters enough to perform a post operative cystoscopy to verify that both ureters remained functional.  We verified that the only dye available to us was indocyanine green and methylene blue.   I was given methylene blue and injected 3 1/2  mLs.  After 20 minutes, no visible dye appeared in the bladder and the procedure was terminated with the plan to follow carefully her course.

    There are three common dyes that anesthesiologist are asked to inject patients in order for diagnostic purposes.  The anesthesiologist should have familiarity with the properties of any medication they inject.  A review of information on these dyes revealed a deficit in my own knowledge in this regard.

    Methylene Blue can be used to test ureteral patency after laparoscopic surgery.  However, it is not commonly used for this indication.  The recommended dose is 50 mg (it comes as a 10mg/mL concentration) for this purpose.  Methylene blue does not have FDA approval for this use, and the package insert only asserts its use as a treatment for methemoglobinemia.

    Methylene blue is the only medication known to be effective for the treatment of methemoglobinemia, which is the oxidation of the iron in hemoglobin to the ferric form.  Normally, the blood has a 1% concentration of methemoglobin (hemoglobin in the ferric form).  When the concentration of methemoglobin rises to about 15%, symptoms become apparent and require treatment.  The negative effects of this disorder result from hypoxia, as oxygen cannot be efficiently carried by methemoglobin.  Symptoms include ashen color skin or cyanosis (methemoglobin from 3 to 20%), headache, dyspnea, lightheadedness (up to 50%), arrhythmias, unconsciousness etc (greater than 50% methemoglobin level).  Treatment dose of methylene blue is 1 mg to 2 mg/kg.  Ironically, at doses greater than 7 mg/kg can lead to the inducement of methemoglobinemia.

    Methylene blue inhibits monoamine oxidase enzyme, and therefore, can result in serotonin syndrome and should be used if with caution in patients taking serotonin reuptake inhibitors or MAO inhibitors.

    As methylene blue can be used for verification of ureteral patency via cystoscopy as the urine should turn blue after 10 to 20 min of IV injection, I thought it curious that we had no evidence of blue urine after 30 min.  However, joel et al. did publish a look at two cases where injection of methylene blue did not result in any change in urine color [1].  The authors suspected that rapid metabolism of methylene blue to leulomethylene (a colorless metabolite was the cause of this anomaly).  Since indigo carmine does not undergo any metabolism prior to excretion into the urine, it would be a superior alternative to methylene blue for detection of ureteral patency using cystoscopy.  Indigo carmine's package insert asserts its primary use is for detecting change in urine color after IV injection.  There are no drug interactions with indigo carmine, making it a safer alternative as well. The dose recommended is the full 5  mL ampule.

    Indocyanine Green is another dye that may be encountered.  It's used for determination of cardiac output, hepatic function and ophthalmic angiography (5mg, 0.5 mg/kg, and 40 mg respectively).  It is bound to plasma proteins and taken up by hepatocytes without metabolism, and secreted in the bile unchanged.  There are reports of the use of indocyanine green to detect ureteral patency via cystoscopy, however, it has been reported to be used in robotic surgery to detect ureters with near infrared light with success.  However, the dye was injected directly into the ureters.  Recently, I was involved in a case where a patient had an internal hernia with small bowel strangulation leading to questionable viability of the small bowel. Indocyanine green was injection IV and a laser was used to evaluate blood flow and vascular patency to the bowel.  This technique is known as laser florescence angiography and uses the florescence properties of indocyanine green to visualize vessels that need to be verified as patent.  With the laser set in place, the room lights off, an injection of indocyanine green is given IV, and within a few moments, the area of interest should light up white on the proper viewing screen where vessels are patent.  Using this technique, we the surgeons were quickly able to verify that all vessels to the bowel section of interest were patent.

    Anesthesiologists are often asked to inject substances that lie outside our typical armamentarium.  We have an obligation to understand the possible ramifications of what we inject, and not always assume that it is proper and safe.

    Joel AB, Mueller MD, Pahira JJ, Mordkin RM. Nonvisualization of intravenous methylene blue in patients with clinically normal renal function. Urology 2001; 58: 607vii. - See more at:

    July 7, 2016

    end tidal CO2, what intraoperative role can it play?

    Today I had a 64 year old male, with no reported medical history, who presented for L4-5 laminectomy.  The patient reported that he walked regularly, up to 2 miles with no history of SOB, chest pain or other symptoms.  The patient was taken to the OR and given 2 mg versed, 100 mcg fentanyl, 180 mg propofol, 5 mg rocuronium, and 100 mg succinylcholine.  IV decadron was also given (8mg).  Intubation proceeded without event and the patient was placed in the prone position.  After turning prone, several issues arose at the same time.  First, pulse oximetry revealed 93% saturation.  Simultaneously, the blood pressure read 50/20 mmHg. ECG appeared normal with SR at 74 bpm.  The pulse plethysmograph waveform appeared robust without obvious issues aberrations.
    Ausculation of the lungs was challenging due to a large tissue mass making breath sounds difficult to detect.  However, it was noted by myself, that there appeared to be no breath sounds on the left, and therefore, the ETT was pulled back slightly.  This resulted in an improvement of the arterial saturation as measured by pulse oximetry.  However, simultaneous troubleshooting of the significant apparent hypotension occurred.  The blood pressure cuff was recycled, and low blood pressure was verified.  Also of note, the capnogram was reading 20 mmHg.  The patient was noted to be ventilated at 700 mL with RR of 10.  The patient weighed approximately 100 to 105 kg. It was immediately apparent that elevated minute ventilation was not likely the sole contributor to the issues related to the hypocapnea.

    While multiple issues were at play at once in this case (endobronchial intubation along with severe hypotension), a deeper exploration of how the capnogram can be helpful in the diagnosis of the issues  at hand.

    In general, end tidal carbon dioxide (etCO2), is a function of PaCO2.  However, a multitude of parameters can cause a gap (this is dead space [Vd], written as (a-ET)PCO2).  In general, healthy patients without significant lung disease will have up to a 5 mmHg difference, where the etCO2 will be less than actual measure PaCO2.    This gap increases with age, emphysema or any state that increass dead space ventilation (Vd), like low cardiac output (from hypovolemia) or pulmonary embolism.  On the other hand, (a-ET)PCO2 can actually be positive (i.e. etCO2 is greater than PaCO2) in pregnancy and children (from 1 to 3 mmHg). In general clinical practice, we do not have access to the (a-ET)PCO2 because we do not routinely measure arterial blood gases.  However, we do follow the trend of the etCO2, and thus, in general, if we see a sudden decrease in the etCO2 on the capnogram, we assume that we may be hyperventilating the patient, or that there has been a sudden increase in dead space ventilation.  However, it must be understood, that there are several parameters other than Vd that can cause a decrease in etCO2. For example, decrease in metabolism or VCO2 will result in decrease in etCO2 if minute ventilation is constant. VCO2 is a function of depth of anesthesia relative to surgical stimulus, and body temperature.  Alternatively, an increase in minute ventilation, if metabolic rate is constant will cause etCO2 to decrease.  Importantly, the (a-ET)PC02, will remain the same in the two above situations.  Another, more sutbtle and less recognized mechanism for (a-ET)PCO2 to be affected is via FiO2.  Yamauchi et al. demonstrated that increasing the FiO2 from room air to very high caused an ever increasing (a-ET)PCO2. [8] They found that Vd increased as the FiO2 was increased in their anesthetized patients.  They presumed that the mechanism of the increase in Vd was an increase in pulmonary vascular dilation with increased oxygen tension.  This occurs predominantly in highly perfused alveolar units resulting in a shunt of blood away from low perfused alveolar units to high perfused alveolar units.  Of course, this shunt created from increasing FiO2 is not related to physiologic shunts that might occur with something like ARDS.  In this case, only large shunts of greater than 30 to 40% will cause a significant change in the (a-ET)PCO2.

    However, a state of low cardiac output can also result in a reduced pulmonary artery blood flow. This results in increased Vd, and thus the (a-ET)PC02 increases.  This manifests in the operating room as a sudden decrease of etCO2.  This pattern was looked at by Askrog and colleagues where an inverse linear correlation was found between pulmonary artery pressure and (a-ET)PCO2. [1]     Things that can cause this include pulmonary emboli (air, debris, clots), sudden massive hemorrhage leading to reduced venous blood return, vasodilation, mechanical obstruction to blood flow, reduced cardiac contractility, etc.  In general, in the OR, mechanical ventilation and anesthetic depth are maintained at a reasonably constant level allowing us to remove these as a cause in theory.

    In my patient, the simultaneous low blood pressure and sudden drop in etCO2, indicated two things: the blood pressure was real (i.e. it was not artifactual), and the drop in etCO2 was most likely due to decreased CO, in this case  the cause being overdose of anesthesia. Of course other causes of a precipitous drop in etCO2 include PE or other mechanical obstruction to pulmonary blood flow.  As it turns out the percent decrease in etCO2 is directly correlated with the percent decrease in CO (assuming that the metabolic rate and alveolar ventilation are unchanged). This was demonstrated in an article published in A and A. [2]  It should be noted that after sustained or constant low CO, (i.e. after 10 to 20 min) CO2 begins to accumulate in the peripheral tissues leading to an increase in CO2 delivery to the pulmonary vasculature.  This will cause the etCO2 to return to baseline if all other factors remain unchanged.  The relationship of etCO2 and pulmonary blood flow was also studied in patients coming off cardiopulmonary bypass. [3]  Here, an etCO2 greater than 30 mmHg (the study did not include patients with significant lung disease), was associated with CO of greater than 4 L/min (CI of 2 L/m). When etCO2 was greater than 34 mmHg, pulmonary blood flow (a good surrogate for CO) was greater than 5 L/min. Once again, minute ventilation was carefully maintained.
    Recently, a large volume of literature has been produced looking at measurements of indices that indicate a patient who is hypovolemic. Pulse pressure variation and stroke volume variation via measurement and analysis of the arterial waveform in ventilated patients in sinus rhythm has proven effective at determing which patients are likely going to respond with increased cardiac output if a fluid bolus is given.  Unfortunately, the equipment is costly, requires a fair amount of data input, and is usually not routinely available. Recently, Monnet et al. [4] was able to show that etCO2 was better than arterial pressure for predicting volume responsiveness when using a passive leg raising test. Using a similar methodology in patients with acute circulatory failure in the ICU, monge garcia et al. showed that etCO2 after passive leg raise maneuver could be used to track changes in CO  for the prediction of fluid responsiveness. [5]  Recently, a group in France was able to demonstrate that after 500 mL hetastarch, an increasae of 2 mmHg in the etCO2 could diagnose fluid responsiveness (specificity 98%, sensitivity 60%). Obviously, it is critical to undertand that other changes to CO2 production and elimination must be held constant for this to be a valid clinical indicator.  It should be recognized that in clinical anesthesia this can be difficult.  In fact, very recently, I took care of patient having an open partial colectomy with small bowell resection.  Her BP trailed lower early in the case.  Based on this article, I decided to carefully track etCO2 and maintain other parameters unchanged (i.e. CO2 production and minute ventilation).  I quickly boluses in 500 mL of hetastarch as used in the above mentioned article.  While I did notice that etCO2 trailed higher with this bolus, I realized that in clinical practice, there are so many other factors occurring that it can be challenging to feel confident that other parameters are not the cause of the change you see reading on the capnogram.   However, importantly,  in this same study, HR variation, MAP variation, and PP variation were not predictive of volume responsiveness. In summary, these authors showed that after a rapid infusion of 500 mL colloid, an increase of 5.8% (or about 2 mmHg) of etCO2 predicted fluid responsiveness in 100% of their patients.  If the etCO2 increased less than 5.8%, no conclusions could be drawn. [6]  In real clinical practice, a bolus must be given very rapidly, to ensure that other parameters don't account for any subtle changes seen on the etCO2.
    Others have demonstrated that etCO2 can be predictive of mortality after out of hospital cardiac arrest (OHCA). In the NEJM [7], an observational study was published looking at etCO2 monitoring following OHCA to determine effectiveness of ACLS.  They found that in this patient population, if  after 20 minutes of ACLS, the etCO2 was less than 10 mmHg, there was a 100% specificity and specificity to determine non survival to hospital admission.  If the etCO2 was greater than 20 mmHg, this indicates survival (at least in this study), but it does not guarantee it.  In this article, it was noted that in low flow states (i.e. low cardiac output), etCO2 becomes a much better surrogate for cardiac output.

    Having an in depth understanding of etCO2 can help us in ways that we might not otherwise expect.

    [1]  Askrog V.  Changes in  (a-A)CO2 difference and pulmonary artery pressure in anesthetized man. J Appl Physiol 1966;;21:1299-1305.
    [2] Shibutani K, Muraoka M, Shirasaki S, Kabul K, Sanchala VT, Gupte P.  Do changes in end-tidal PCO2 quantitatively reflect changes in cardiac output? Anesth Analg 1994;79:829-33.
    [3] Maslow A, Stearns G, Bert A, Feng W, Price D, Schwartz C, Mackinnon S, Rotenberg F, Hopkins R, Cooper G, Singh A, Loring SH. Monitoring end-tidal carbon dioxide during weaning from cardiopulmonary bypass in patients without significant lung disease. Anesth Analg 2001;92:306-13.
    [4] Monnet X, Bataille A, Magalhaes E, Barrois J, Le Corre M, Gosset C, Guerin L, Richard C, Teboul J-L. End-tidal carbon dioxide is better than arterial pressure for predicting volume responsiveness by the passive leg raising test. Intensive Care Med 2013;39: 93–100. 
    [5] Monge García MI, Gil Cano A, Gracia Romero M, Monterroso Pintado R, Pérez Madueño V, Díaz Monrové JC. Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO2 pressure during a passive leg-raising maneuver. Ann Intensive Care. 2012;2:9
    [6] Jacquet-Lagreze M, baudin F, David JS, Fellahi JL, Hu PB, Lilot Ma, Piriou V. End -tidal carbond dioxide variation after a 100- and a 500-ml fluid challenge to assess fluid responsiveness.  Annals of Intensive Care 2016 6:37.
    [7]Levine R, et al. End Tidal Carbon Dioxide and Outcome of Out-of-Hospital Cardiac Arrest. NEJM; 337(5):301.
    [8] Yamauchi H, Ito S, Sasano H, Azami T, Fisher T, Sobue K.  Dependence of the gradient between arterial and end-tidal PCO2 on the fraction of inspired oxygen.  BJA. 2011.107(4):631-5.