Calcium gluconate in a digitalised heart with hyperkalemia! OK...or..NOT OK???

Today's morning report was about a young guy who was admitted with rhabdomyolysis, renal failure and hyperkalemia(K- 12mEq/dl) with sine wave pattern on his EKG. All this was due to a electrocution injury.So ...going through the management of hyperkalemia, someone pitched in the problem of giving Calcium gluconate in patients on Digoxin. Well....we had a couple of explanations for the interaction.So lets review the problem with these two drugs together.
First.....the mechanism of action of Digoxin- Digoxin inhibits the Na⁺/K⁺-ATPase(exchanges 2 K for 3Na) in the cardiac myocyte by competing with potassium,and causes intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium by blocking the Na⁺-Ca⁺⁺ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).


Second.....the mechanism of action of Calcium gluconate- a litlte more cellular pathology! . Normally the cardiac myocyte has a resting membrane potential(RMP is -90mV) and a threshold potential at which it is excited(TP is-75mV).So a 15mV depolarisation is needed to excite the myocyte. In hyperkalemia, the RMP becomes less negative (-80mV) , but the TP remains at -75mV. This means that ..now..only a 5mV depolarisation is enough to excite the myocyte. This is the cause of hyperexcitability leading to arrhythmia.Calcium gluconate...by increasing Ca transport across the membrane reduces the TP from -75mV to around -65mV ...restoring the 15mV depolarisation needed to excite the myocyte. (the numbers in mV are just an example)  ...... Annals of Emer Med 2011


Sooo...in patients on Digoxin(which causes positive inotropy through calcium)...if more calcium is given....it can lead to more intracellular calcium in mycocyte leading to what has been described as cardiac tetany due to prolonged depolarisation. So ,does hyperkalemia make this process worse?? Well, probably not. ------Since K+ and digoxin compete for Na/KATPase, the binding depends on the concentration of the two. In hyperkalemic state...K+ binds preferentially than digoxin, on Na/K ATPase, and thus resulting in diminished digoxin action. (to better understand...think about hypokalemic states...where digoxin will bind preferentially to the receptor, and hence result in digoxin toxicity!--which is well known)
A slightly different scenario would be...when some one(with no K+ problems) takes too much digoxin...which will also result in digoxin binding preferentially than K+,  to Na/KATP ase resulting in Dig toxicity. In this setting....pt may go hyperkalemia..as more K+ ends up extracellularly (due to not binding with Na/K ATPase), and if this patient gets Ca gluconate..then again..it can causes arrhythmias.


Bottom line is...if Calcium is given(and pt made hypercalcemic) to any pt on Digoxin ..there is a increased possibility for cardiac arrhythmias(PG Med J 1999) ...irrespective of whether they have hyperkalemia or not. 
Whether these pathophysiologies!! are clinically relevant is not clear, as these interactions are based on few case reports only. Have a look at this animal study (J clin Tox 2004) and this retrospective study on pts ..over 18 years from a hospital in Arizona(J Emer Med 2011).Both of them show no clinically relevant interaction of Calcium administration even in Digoxin toxicity.     !!!!!!!

Some key aspects of Surviving sepsis

The key recommendations covering all aspects of sepsis treatment were outlined in the 2008 update on Surviving sepsis campaign. This is a tribute to my 2 month CU rotation which I completed this week.....


Early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C)
Blood cultures before antibiotic therapy (1C);
 Imaging studies performed promptly to confirm potential source of infection (1C); 
Administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D);
 Reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D);
 Source control with attention to the balance of risks and benefits of the chosen method (1C);
 Administration of either crystalloid or colloid fluid resuscitation (1B);
 Fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); Vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C);
 Stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); 
Recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients).
 In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B);
 A low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); 
Application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A);
 To decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C);
 Protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B);
Institution of glycemic control , targeting a blood glucose <150 mg/dL after initial stabilization (2C);
 Equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); 
prophylaxis for deep vein thrombosis (1A); 
Use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D).


Our hospital has a Sepsis alert system whereby anyone getting into ER with tachycardia and fever will be eligible for a STAT call to the ICU resident (which was unfortunately 'I' for the last 2 months!!). http://www.survivingsepsis.org/About_the_Campaign/Documents/Final%2008%20SSC%20Guidelines.pdf

complications during rewarming

Therapeutic rewarming is being used widely in patients after a cardiac arrest (irrespective of type of cardiac arrest). Earlier the patient is cooled ..better the neurological outcome. Usually we keep them under hypothermia for 24 hours. Then comes the period of rewarming, which can be safely done by reducing the body temperature by 0.3 - 0.5 C /hr...and the aim is to normalise body temparature by 8 hours after starting to rewarm. Hemodynamic instability /electrolyte derangements/ arrhythmias can occur during this period...and should be addressed sooner than later.

Medications During Rewarming
Maintain sedation until a temperature of 35° C (95° F) is reached.
- If a neuromuscular blocking agent is infusing solely  to prevent shivering, discontinue the neuromuscular blocking agent before the sedative/analgesic agents.
- Do not discontinue the sedative/analgesic until the patient is moving or until the neuromuscular blocking agent has been discontinued for at least 3 to 5 half lives of the paralytic.


Hemodynamics
Monitor patient for hypotension. This is secondary to peripheral vasodilatation induced by rewarming. Gentle i.v fluids helps with this issue. Its physiologically reasonable ..not to use Ringer Lactate in this situation, as the hypothermic liver would not be able to metabolise lactate. Try to avoid vasopressors like dopamine during this period..due to the cardiac excitability from these drugs. Again ...physiologically phenylephrine would make more sense as it does not have a beta activity..and only has alpha atction.


Electrolytes
Discontinue potassium infusions during rewarming as potassium moves out of cells into the extracellular space.
Acetaminophen and external cooling p.r.n. to keep temperature less than 37.5° C (99.5° F) for 48 hours after  warming. 

Fondaparinux(Arixtra) and a word of caution

This summary is not available. Please click here to view the post.

Does Cranberry Juice Prevent Recurrent UTI ?

As we all know....cranberry juice has been thought to prevent UTIs. No we have a randomised controlled trial to answer the above question. Reasearchersa at Michigan conducted a double blind trial on women 18 - 40 years of age who presented with with UTIs over a 2 year period.

There were 319 participants who were randomized to receive 8 ounces twice daily of placebo juice or of low-calorie cranberry juice cocktail standardized for its concentration of proanthocyanidin (the active ingredient). A clean-catch urine sample was collected for culture at baseline, 3 months, and 6 months, and at visits associated with UTI episodes. During the 6-month follow up, 54 culture-confirmed recurrent UTI episodes were observed. The recurrence rate — 16.9% overall — was 19.3% in the cranberry juice group and 14.6% in the placebo group (P=0.21).

These findings and the don't show any reduction in the recurrence of UTI among reproductive age group females. However, as the authors point out, something other than proanthocyanidin might be the active factor, and the placebo might inadvertently have contained this ingredient. Therefore, this study is probably not the last nail on cranberry juice and UTI prevention.In fact the 2008 cochrane review  showed a small reduction in UTI over a 12 month period.

After an initial urinary tract infection (UTI), 24% of otherwise healthy women aged 18 to 39 experience a recurrence within 6 months, and 5% of women have multiple recurrences within 1 year. Cranberry juice is a well-known folk remedy for preventing UTI, and in vitro experiments have suggested that cranberries decrease the adherence of Escherichia coli to the uroepithelium.

All this study shows is that proanthocyanidin may not be the active ingredient behind UTI prevention ! Given the inability to prove or disprove this theory........it will be ok to take cranberry juice....as it doesnt cause any harm.

angioedema risk with ace-inhibitors

We recently had an african american male presenting with swollen tongue, lips and a stridor. was intubated for airway compromise..given epinephrine im, benadryl, ranitidine, hydrocortisone. Was extubated the next day after resolution of edema. This gentleman was started on Lisinopril 2 weeks ago for hypertension. This is likely...to be Angioedema due to ace-i!!


The pathophysiologic mechanism of angioedema with regard to ACE inhibitor therapy is believed to relate to the kallikrein-kinin plasma effector system. Bradykinin, which is normally degraded by kininase II/ACE, accumulates in tissues pts on ace-i.  Plasma bradykinin has been shown to increase up to 12-fold during acute angioedema attacks in patients with hereditary or acquired forms of angioedema. A case control study from 1997 showed consistently decreased levels of carboxypeptidase N(kininase1) and C1 esterase inhibitor in pts with angioedema secondary to ace-i Vs pts without angioedema on ace-i.

Another interesting theory has been the association of low levels of dipeptidyl peptidase 4( known to catabolise bradykinin) in pts with ace-i associated angioedema. (Hypertension 2002). The reason this is interesting is because ..... the recent DPP-4 inhibitors(Sitagliptin, Saxagliptin) that we use for diabetes work by inhibiting DPP-4. So if the above theory is true..then we might see an increased risk of angioedema in patients on these medications along with ace-i(as most diabetics need ace-i). Lets wait and see!!!!


Several risk factors for development of angioedema with ace-i have been proposed.The most important predisposing risk factor, evidenced by case-control studies, appears to be ethnic differences.The risk of angioedema with ACE inhibitors is higher in blacks and appears not to be related to dose, specific ACE inhibitors, or concomitant medications...as shown in this nice case control study(Clin Pharm & Ther 1996). Other risk factors are a history of idiopathic angioedema, head and neck surgery, and seafood allergy. 


This study from 1988 ...which looked at 3 studies...each with 12,0000 patients.....showed that the incidence of angioedema is high in the first week of starting Enalapril...and then declined. But previous tolerance to an ACE inhibitor does not exclude the risk for angioedema when therapy is modified to a different ACE inhibitor. Finally...the oberall incidence of angioedema with ace-i is around 0.1 - 0.6% over a period of 6 months (a rough estimate based on studies like OCTAVE  (again showing a higher incidence among African americans than other races)

Amiodarone and hyperthyroidism

Amiodarone therapy causes thyroid dysfunction in 14 to 18% of the involved patients. Therefore, before initiation of such therapy, patients should have a baseline TSH measurement, and then they should be monitored at 6-month intervals during treatment.

In patients receiving amiodarone, either hypothyroidism, which is treated with levothyroxine replacement, or hyperthyroidism may develop.

Amiodarone-induced hyperthyroidism is of two types.

Type 1 is similar to iodine-induced hyperthyroidism (jodbasedow phenomenon) and manifests with a low TSH level, a high free T4or T3estimate, and a low radioiodine uptake. Doppler ultrasonography shows increased vascularity of thyroid tissue, similar to that in Graves’ disease. Because of low radioiodine uptake,  131I treatment cannot be used, and use of antithyroid drugs has yielded only varied success. Although mild cases have resolved even when amiodarone therapy has been continued, consideration of ceasing this drug treatment is recommended. Restoration of euthyroidism may take months after cessation of amiodarone therapy.

Type 2 amiodarone-induced hyperthyroidism resembles a destructive thyroiditis. Laboratory values and radioiodine uptake are similar to the findings in type 1; however, Doppler ultrasonography shows decreased vascularity of the thyroid tissue. Corticosteroid treatment is recommended, and patients sometimes require surgical removal of the thyroid.

Wherever possible its better to avoid ..than to treat this complication!!